Antibiotics 09 00119 With Cover

5.
222
Review
Insights into Acinetobacter

baumannii: A Review of
Microbiological, Virulence, and
Resistance Traits in a Threatening
Nosocomial Pathogen
Carole Ayoub Moubareck and Dalal Hammoudi Halat
Special Issue
Targeting β-lactamases to Fight Bacterial Resistance to β-lactam Antibiotics
Edited by
Dr. Cecilia Pozzi
https://doi.org/10.3390/antibiotics9030119
antibiotics
Review
Insights into Acinetobacter baumannii: A Review of
Microbiological, Virulence, and Resistance Traits in a
Threatening Nosocomial Pathogen
Carole Ayoub Moubareck 1, *,† and Dalal Hammoudi Halat 2,†
1 College of Natural and Health Sciences, Zayed University, Dubai P.O. Box 144534, UAE
2 Department of Pharmaceutical Sciences, School of Pharmacy, Lebanese International University, Beirut,
Bekaa Campuses 1103, Lebanon; [email protected]
* Correspondence: [email protected]; Tel.: +971-4-402-1745
† Authors contributed equally to the manuscript.

Received: 3 February 2020; Accepted: 2 March 2020; Published: 12 March 2020
Abstract: Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the
major causes of nosocomial infections in the current healthcare system. It has been recognized as an
agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated
with high mortality. Pathogenesis in A. baumannii infections is an outcome of multiple virulence
factors, including porins, capsules, and cell wall lipopolysaccharide, enzymes, biofilm production,
motility, and iron-acquisition systems, among others. Such virulence factors help the organism to resist
stressful environmental conditions and enable development of severe infections. Parallel to increased
prevalence of infections caused by A. baumannii, challenging and diverse resistance mechanisms in
this pathogen are well recognized, with major classes of antibiotics becoming minimally effective.
Through a wide array of antibiotic-hydrolyzing enzymes, efflux pump changes, impermeability,
and antibiotic target mutations, A. baumannii models a unique ability to maintain a multidrug-resistant
phenotype, further complicating treatment. Understanding mechanisms behind diseases, virulence,
and resistance acquisition are central to infectious disease knowledge about A. baumannii. The aims
of this review are to highlight infections and disease-producing factors in A. baumannii and to touch
base on mechanisms of resistance to various antibiotic classes.
Keywords: Acinetobacter baumannii; multidrug resistance; virulence factors; antibiotics; pathogenesis
1. Introduction
Over the last decades, Acinetobacter baumannii has globally emerged as a highly troublesome
nosocomial pathogen. Its clinical significance has been largely driven by a remarkable ability to acquire
or upregulate various resistance determinants, making it one of the most successful multidrug-resistant
(MDR) organisms threatening current antibiotic therapy [1]. On top of such fascinating resistance
acquisition, A. baumannii is endowed with multiple mechanisms of survival under a wide range of
environments, potentiating capacity for hospital spread [2]. The attributable mortalities in patients
with A. baumannii healthcare-associated infections, of which ventilator-associated pneumonia and
bloodstream infections are the most common, can range from 5% in general hospital wards to 54%
in the intensive care unit (ICU) [3], with increasing reports of community-acquired A. baumannii
infections [4]. Mounting evidence of extensively drug-resistant (XDR) and pandrug-resistant (PDR)
isolates of A. baumannii is also accumulating in different countries [5–7]. The World Health Organization
(WHO) has assigned A. baumannii as a critical priority pathogen posing a great threat to human health,
and towards which new antibiotics are urgently needed [8]. Such clinical and public health implications
Antibiotics 2020, 9, 119; doi:10.3390/antibiotics9030119 www.mdpi.com/journal/antibiotics

Antibiotics 2020, 9, 119 2 of 29
underlie the need to further understand and evaluate both disease and antibiotic resistance mechanisms
in this pathogen. The aims of the current review are to highlight clinically relevant infections and
disease-producing factors in A. baumannii, and to revise its mechanisms of resistance to various
antibiotic classes.
2. Taxonomy and Microbiological Properties of Acinetobacter baumannii

The current definition of the genus Acinetobacter consists of short, pleomorphic coccobacilli that
are Gram-negative, strictly aerobic, catalase-positive, oxidase-negative, nonfermenting, and nonmotile.
Their DNA G+C content ranges between 39% to 47%. Acinetobacter produces at 37 ◦ C grayish-white,
smooth, mucoid colonies on solid media commonly used for diagnostic purposes, like sheep blood
agar and tryptic soy agar [2].
After its first description at the beginning of the 20th century, this heterogeneous group of bacteria
has gone through a remarkable, complex, taxonomic history. Since the 1980s, and in correspondence to
wide recognition and emergence of acinetobacters as nosocomial pathogens, refined taxonomy has been
constantly updated [4]. Thanks to the work of Bouvet and Grimont [9], an initial landmark classification
of acinetobacters was based on DNA–DNA hybridization studies, and distinguished 12 DNA groups
or genospecies, some of which were given formal names like A. baumannii, Acinetobacter calcoaceticus,
Acinetobacter haemolyticus, Acinetobacter johnsonii, Acinetobacter junii, and Acinetobacter lwoffii. As of 2019
and according to a review published by Vijayakumar et al., 59 species belong to the genus Acinetobacter,
where 11 have defined names and 15 have a tentative description [10]. In particular, the Acinetobacter
calcoaceticus–Acinetobacter baumannii complex (ACB complex) comprises four species: A. calcoaceticus
(genomic species 1), A. baumannii (genomic species 2), Acinetobacter pittii (previously genomic species 3),
and Acinetobacter nosocomialis (previously genomic species 13 TU) that are closely related and difficult
to distinguish by phenotypic properties [11]. Recently, two new species, Acinetobacter seifertii and
Acinetobacter dijkshoorniae, were also included within the ACB complex. Hence, the ACB complex
collectively includes five Acinetobacter species associated with human diseases (A. baumannii, A. pittii,
A. nosocomialis, A. seifertti, and A. dijkshoorniae) and one environmental species (A. calcoaceticus), which is
commonly isolated from soil and has not been described as a human pathogen [12,13].
The identification of Acinetobacter to the species level remains complicated and challenging.
Phenotypic methods based upon growth temperatures, hemolysis, glucose acidification,
and carbon/energy sources [10], in addition to commercial automated systems [14], are proposed.
Molecular species identification by DNA–DNA hybridization studies [15], 16S rRNA sequencing [16],
and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) [17]
are increasingly being used. In addition, there is a transition from traditional typing methodology
to whole-genome sequencing-based approaches that are proving their utility in epidemiological
classification of Acinetobacter. Performance of such methods demonstrates superiority to conventional
typing and promises useful future incorporation in infection control besides current use in
epidemiological research [18,19]. A reliable biomarker for identification of the species A. baumannii is
the blaOXA-51-like gene, chromosomally located in this species and displaying very weak hydrolysis of
carbapenems [20]. The utility of this gene for differentiation of A. baumannii from ACB complex has
been elaborated by Turton and colleagues [21].
A. baumannii, A. pittii, and A. nosocomialis are still difficult to precisely identify in most laboratories
and they represent the three most clinically relevant species of Acinetobacter that have been implicated
in the vast majority of both community-acquired and nosocomial infections [4]. Hence, this review
will use A. baumannii in the comprehensive sense to refer to these three species.
3. Associated Infections and Clinical Impact of A. baumannii

As mentioned above, A. baumanni has propensity to tolerate stressful environments and multiple
classes of antibiotics, making it able to survive and spread as a nosocomial pathogen, particularly
in critically ill patients, contributing to increased morbidity and mortality [22]. Previous studies
addressing risk factors for acquisition of A. baumannii have reported multiple culprits including long
ICU stay, previous hospital or ICU stay, previous antimicrobial therapy, mechanical ventilation, use of
devices (indwelling catheters, endotracheal tube or nasogastric tube), older age, major or emergent
surgery, low birth weight or prematurity, dialysis, and prolonged use of total parenteral nutrition
or intravenous lipids [23–26]. In recent years, A. baumannii infections involving respiratory tract,
bloodstream, skin and soft tissue, urinary tract, and central nervous system have emerged as highly
problematic in healthcare institutions. Figure 1 summarizes A. baumannii disease burden, resistance,
and endemicity in humans, animals, and the environment.
Figure 1. The dynamic microbiological nature of Acinetobacter baumannii derives from an interplay
between the associated infections, wide arsenal of virulence factors, multidrug-resistant phenotype,
and spread in animals and the environment.
3.1. Respiratory Infections

Ventilator-associated pneumonia (VAP) caused by MDR A. baumannii remains a leading cause of
high mortality rate in critically ill patients [27]. A. baumannii accounts for 8% to 14% of VAP in the
United States and Europe, but this pathogen is associated with higher rates (19% to >50%) in Asia,
Latin America, and some Middle Eastern countries [28]. Recent research indicated that incidence of
MDR A. baumannii transmission was 315.4 cases/1000 ICU patient-days with mortality rate ranging
from 52% to 66% [29]. In a seven-year survey of MDR A. baumannii infections in a tertiary care center
in Lebanon, the most common site of infection among the isolates was the respiratory tract (53.1%),
followed by surgical wound (18.8%), blood (15.6%), urine (10.2%), and others (2.3%). The most common
colonization site was the respiratory tract (80.8%) followed by skin colonization (12.4%) [30]. In a more
recent investigation from a university hospital, rates of MDR, XDR, and PDR A. baumannii recovered
from VAP cases were 13.3%, 68.3%, and 18.3%, respectively, with female gender and red blood cell
transfusion as independent risk factors for mortality [31]. Furthermore, a predominant clonal lineage
of A. baumannii was found to be associated with VAP across 12 hospital centers in three European
countries, and suggests the emergence of a XDR/PDR A. baumannii epidemic, with resistant rates close
to 100% for carbapenem and 50% for colistin [32]. In a recent meta-analysis involving 29 countries,
the prevalence of MDR phenotype among A. baumannii causing hospital-acquired pneumonia and
VAP was close to 80%. Central America, Latin America, and the Caribbean had the highest prevalence,
whereas Eastern Asia had the lowest [33]. Also, in a screening analysis for lower respiratory tract
specimens of 97 patients infected with A. baumannii in Southern Vietnam, 80% of the specimens were
carbapenem resistant and 90% were MDR [34].
Although A. baumannii-induced VAP appears to have a predilection for vulnerable patients,
community-acquired pneumonia (CAP) due to this organism is an increasing cause for concern. It is
characterized by a fulminant course, high incidence of bacteremia, and high mortality rate, especially in
tropical regions, where it predominantly affects individuals with excess alcohol consumption, diabetes
mellitus, smoking, and chronic lung disease [35]. CAP caused by A. baumannii is prevalent in different
parts of Australia, Oceania, and Asia, including Taiwan, China, and Thailand [36]. A recent Chinese
study reported A. baumannii CAP caused by a rare sporadic clone of sequence type 880 that carries the
plasmid-encoded blaOXA-72 gene conferring resistance to carbapenems [37]. Accumulating scientific
evidence about the role of A. baumannii in respiratory tract infections needs to be put in perspective for
better surveillance and control.
3.2. Bloodstream Infections

A. baumannii has become a leading cause of bloodstream infections in health care settings with
intravenous catheters or the respiratory tract representing a frequent source of infection. Mortality rate
due to bloodstream infections caused by A. baumannii is approaching 40% [38]. High incidence of
bacteremia due to A. baumannii has been reported in cancer patients, where this organism accounted for
about 68% of bacteremia cases in a Brazilian study. Unfortunately, such bacteremia had a high mortality
among cancer patients, and risk factors associated with infection-related mortality appeared to be more
closely linked to management of bacteremia than to special characteristics of the cancer population,
such as neutropenia and tumor site infection [39]. In another category of patients, namely those
undergoing neurosurgery, about 13% of bloodstream infections over a period of 10 years were attributed
to A. baumannii, of which 90% were carbapenem resistant [40]. In another study discussing severely
burned patients admitted to a burn ICU, A. baumannii was the top isolated pathogen from blood for four
consecutive years, and except for low resistance profile to polymyxin B and minocycline, the isolates
were almost 100% resistant to other antibiotics [41]. In a recent study from a hospital in Northwest
Ethiopia, A. baumannii accounted for about 9% of nosocomial bloodstream infections, and were 100%
resistant to ampicillin and piperacillin, and 33.3% and 44.5% resistant to meropenem and ciprofloxacin,
respectively [42]. Moreover, 42% of A. baumannii causing bloodstream infections in ICU patients from a
Greek university hospital were resistant to colistin, and were directly linked to fulminant septic shock
and high mortality [43]. Such wealth of data regarding the upsurge of drug-resistant A. baumannii
in bloodstream infections, especially in severely ill patients, requires emphasis on surveillance and
characterization of antimicrobial resistance patterns, as well as reinforcement of appropriate antibiotic
and infection control measures.
3.3. Skin and Soft Tissue Infections

A. baumannii has been repeatedly isolated from skin and soft tissue in patients with severe
burns, wounds, or trauma, for instance, soldiers injured during military operations or victims of
natural disasters. A landmark paper by Davis and colleagues [44] reported war wound infection and
osteomyelitis caused by MDR A. baumannii during the 2003–2005 military operations in Iraq. In another
retrospective study of US military service members wounded in Iraq or Afghanistan, A. baumanniii
was the most commonly isolated pathogen from open tibial fractures [45]. Afghanistan and Iraq
remain the two major geographic locations where A. baumannii were isolated from wound or soft
tissue especially after traumatic injury [36]. In a military medical center in the US, overall A. baumannii
isolation increased from 4% to 55% over eight years, with wound isolates accounting for 24% of
total A. baumannii specimens. Moreover, the percentage of MDR A. baumannii isolates recovered
was higher among combat casualties deployed overseas (52%) than among local patients (20%) [46].
Among military patients from a tertiary care burn center, patients with A. baumannii infection had more
severe burns and comorbidities, longer lengths of stay, and higher mortality compared to patients
without infection [47]. Therefore, and specifically to military personnel with war wounds, A. baumannii
represents a challenging threat, and should be prevented by combating nonhealing wounds that are
likely to develop wound biofilms (described shortly) with prominent antimicrobial resistance [48].
In one study about Gram-negative osteomyelitis in Brazil, A. baumannii caused 21% of cases, and 40% of
the isolates were carbapenem resistant [49]. Furthermore, in China, and after the Wenchuan earthquake,
about 14% of wound infections in trauma patients were caused by A. baumannii [50].
3.4. Urinary Tract Infections

Although research on A. baumannii infections has primarily focused on pneumonia and bloodstream
infections, recent claims are that one in five A. baumannii strains are isolated from urinary sites [51].
A. baumannii occasionally causes urinary tract infections (UTIs), especially with indwelling urinary
catheters [4], and was responsible for 1.6% of ICU-acquired UTIs in one study [52]. Balfousias and
colleagues reported a PDR strain of A. baumannii causing urinary tract infection in a 72-year old
patient admitted to a trauma ward of a Greek hospital for femur fracture, and requiring a combination
therapy of rifampicin, tigecycline, and vancomycin in their maximum doses to produce negative urine
cultures [53]. In a study of characteristics of A. baumannii isolated from ICU in 10 hospitals in Korea,
55.6% of the isolates were associated with urinary tract infection. Of these isolates, 19.8% were resistant
to imipenem and 25% to meropenem, 13.5% to polymyxin B, and 17.7% to colistin [54]. Moreover, it is
unusual for this organism to cause uncomplicated UTI in healthy outpatients [2].
3.5. Meningitis
Nosocomial meningitis due to A. baumannii remains an increasing threat in intensive
care neurosurgery units, with mortality approaching 70%, especially in patients on indwelling
ventriculostomy tubes or cerebrospinal fistulae and receiving post-surgical antimicrobial therapy [55].
The largest case series of postneurosurgical A. baumannii meningitis published in 2019 revealed that
21% of isolates had XDR phenotype with sensitivity to only colistin and tigecycline. Furthermore,
age over 40, presence of external ventricular drain, raised cerebrospinal fluid white blood cell count,
and presence of comorbidities (diabetes and hypertension) were risk factors for mortality due to
A. baumannii in the neurosurgical ICU [56]. In a review of pediatric meningitis cases caused by
A. baumannii in China, cultures of cerebrospinal fluid yielded MDR, XDR, and PDR A. baumannii
following neurosurgery, with high mortality rate [57]. In another report from China, and in a university
hospital, the prevalence of MDR and XDR A. baumannii infection among patients with intracranial
infection after a neurosurgical operation was 33.64%. The isolates were 100% resistant to imipenem and
meropenem, 98.38% to cefazolin, 100% to ceftazidime, 100% to cefatriaxone, and 98.39% to cefepime,
but completely sensitive to polymyxin B, 60.66% to tigecycline, and 49.18% to amikacin. No significant
differences in basic clinical data were observed between the two groups [58].
4. A. baumannii Virulence Factors

In recent years, approaches involving genomic, phenotypic, and infection model analyses helped in
the identification of virulence factors important for A. baumannii pathogenicity [22]. Current consensus
supports a multifactorial and combinatorial strategy, with about 16 identified gene islands implicated in
virulence, signifying that the organism devotes a considerable portion of its genes to pathogenesis [59].
Systematic studies failed to identify a particular virulence factor responsible for clinical success of
A. baumannii. This perspective highlights strong adaptive potential and could be a result of adaptation
to different human body sites or pathogenic strategies, as known for other bacteria like Escherichia
coli and Legionella [60]. An illustration of virulence determinants identified in A. baumannii so far is
discussed below and is curtailed in Figure 2.
Figure 2. An illustration of virulence determinants possessed by Acinetobacter baumannii. The function

of each determinant is shown in the adjacent box. AceI = Acinetobacter chlorhexidine efflux
protein; CpaA = glycan-specific adamalysin-like protease; Csu = chaperon/usher pilus system;
LPS = lipopolysaccharide; Omp = outer membrane protein; PNAG = β poly-β-1,6-N-acetylglucosamine;
T2SS = type II secretion system; T6SS = type VI secretion system.
4.1. Outer Membrane Proteins (Porins)

Outer membrane proteins of Gram-negative bacteria generally have a pivotal role in environmental
interaction and adaptation, and are key players in virulence [61]. The main outer membrane protein
OmpA of A. baumannii is involved in cell invasion and apoptosis. This 38kDa protein is vital for
small solute penetration. It binds to host cell surface, gets localized in both mitochondria and nuclei,
and induces cell death [62]. In a study investigating potential of A. baumannii to invade epithelial cells
of a murine pneumonia model, prominent lung histopathologic changes (abundance of white blood
cells and alveolar damage) were detected in mice having wild-type infection but not in those infected
with OmpA- mutants [63]. Besides its transport function as porin, OmpA has the capacity of inducing
host cell apoptosis, biofilm formation, dissemination into bloodstream, and interaction with epithelial
cells mainly using host fibronectin [64].
Another outer membrane protein of A. baumannii is the Omp 33- to 36-kDa protein that acts as a
channel for water and whose expression is associated with resistance to carbapenem antibiotics [65].
In one study, this protein was released in immune and connective cells, where it induced apoptosis
by blockade of autophagy, enabling intracellular persistence with subsequent development of
cytotoxicity [66]. Furthermore, knockout strains of A. baumannii with deficient Omp 33–36 had
defective growth rate and significantly reduced capability of adherence, invasion, and cytotoxicity,
indicating that Omp33–36 plays an important role for fitness and virulence of A. baumannii [65].
Like Omp 33–36, CarO plays also a role in carbapenem resistance in A. baumannii; it was
shown that increased CarO expression delays infiltration of pulmonary neutrophils via attenuation of
proinflammatory responses in the trachea and lungs, allowing bacterial proliferation and resulting in
severe pneumonia [67].
4.2. Cell Envelope Factors (LPS and Capsule)

In Gram-negative human pathogens, the cell wall polysaccharide (LPS) is one of the virulence
factors involved in multiple steps of disease process. A. baumannii LPS is important for resistance to
normal human serum and confers a competitive advantage for survival in vivo. It also can elicit a
proinflammatory response in animal models [68]. The antigenic O-polysaccharide of the LPS, together
with pili, might promote adherence to host cells as a first step of colonization [69].
Beyond the LPS, a major cell structure determinant of A. baumannii virulence is the presence of a
capsule around bacterial surface. The repetitive, closely packed sugar units of the capsule create a
barrier against environmental conditions like dryness and disinfection, and immune system reactions
like phagocytosis; it also protects against some antimicrobials [70,71]. Despite differences in capsular
sugars of A. baumannii, with over 100 variable types, the capsule is perpetually effective for survival of
the pathogen during infections and its ability to grow in serum [72].
4.3. Enzymes
Phospholipases are known additional virulence factors of A. baumannii; these are crucial hydrolytic
enzymes and possess a lipolytic activity against phospholipids of human cell membranes. While the
enzyme phospholipase D helps A. baumannii to persist in human serum as shown in a murine
pneumonia model, another enzyme, phospholipase C, is toxic to epithelial cells [73].
Data about enzymes in A. baumannii continue to culminate; recently, the enzyme CpaA,
a glycan-specific adamalysin-like protease, was identified as a virulence factor that inhibits blood
coagulation through inactivation of factor XII. As such, CpaA attenuates formation of thrombi in
intravascular sites, promoting dissemination capacity of A. baumannii [74].
4.4. Capsular Polysaccharide Composition and Outer Membrane Resistance to Desiccation and Disinfection
Desiccation resistance, or persistence in dry environments, can allow A. baumannii strains to
survive up to 100 days, although this period is variable [75]. A. baumannii environmental survival is
related to presence of capsular polysaccharides surrounding the whole cell and providing defense
against the environment [76]. Resistance to dryness has been linked to outer membrane composition;
a mutant strain of A. baumannii with chemically altered lipo-oligosaccharide was unstable in dryness,
suggesting that fluidity of the outer membrane resulting from changes in its lipid structure allows
escape of water and nutrients to outside of the cell [77].
A. baumannii is shown to actively pump chlorhexidine, an antiseptic used against a wide range
of bacteria by disrupting cell membranes. The Acinetobacter chlorhexidine efflux protein (AceI) is
responsible for such pumping, possibly promoting survival under stressful conditions [78]. On the
other hand, ethanol promotes growth and virulence of A. baumannii [79]. Ethanol in the serum of
alcoholic subjects weakens phagocytosis and hence destruction of the organism [80]. Likewise, excess
human consumption of ethanol is a probable predisposing factor for A. baumannii community-acquired
infections [35].
4.5. Biofilm Production and Quorum Sensing

Among all virulence determinants, biofilm formation has become a major pathogenesis feature for
A. baumannii, making the organism multidrug resistant. By definition, biofilms are microcommunities
of microbes enclosed in an extracellular substance, and rendering microbes resistant to stresses
including desiccation, immune system clearance, and antibiotics [81]. Biofilms additionally mediate
pathogen-host interactions in A. baumannii. Most A. baumannii have a chaperon/usher pilus system,
known as Csu pili, regulated by the BfmRS two-component (TC) system, a network of molecules
that influences gene expression and enables building a protective capsule in response to antibiotics.
The system also mediates pili formation to facilitate cell attachment [82]. Another TC system, GacSA,
can affect Csu gene expression, and therefore may have an indirect influence on the pathogen’s ability
to produce biofilms [83]. A. baumannii is ‘characterized by production of biofilm-associated proteins
(BapAb) similar to Bap protein of Staphylococcus aureus, and that have capacity to aggregate for building
up biofilm matrix in response to stressful environmental conditions [84].
Although most sequenced strains of A. baumannii carry a bap gene, many seem to have
disrupted or truncated bap sequences. Nevertheless, Bap-like proteins, BLP1 and BLP2, may be
encoded by some strains of A. baumannii, and help in maturation of biofilms, like BapAb [85].
Another notable factor that helps A. baumannii to produce biofilm is production of the exopolysaccharide
poly-β-1,6-N-acetylglucosamine (PNAG), which is produced by many Gram-negative species, and is
essential for adhesion and aggregation [86].
Many reports suggest that quorum sensing plays a major role in biofilm formation. Quorum sensing
is a mode of communication among bacteria to maintain population density, usually by production of
signaling molecules known as autoinducers [87]. These are hormone-like compounds, including acyl
homoserine lactones (AHLs), that are responsible to regulate motility, biofilm formation, and other
characteristics. The quorum sensing cycle in A. baumannii includes AbaI inducer as well as its cognate
receptor AbaR. AbaI, encoded by the gene abaI, is a sensor protein that functions as an autoinducer
synthase producing signal AHL molecules, while AbaR functions as a receptor protein, which upon
binding to AHLs induces a cascade of reactions. This binding triggers production of more AHLs in a
positive feedback loop manner, which results in regulation of biofilm formation [88].
4.6. Motility
Bacterial motility contributes to the infectious ability and increased virulence of some bacteria [89].
A. baumannii lacks flagella and has been long labeled as non-motile [90,91]. However, studies show
that this organism can survive during infection and can spread on surfaces during hospital survival by
using twitching motility [92]. Such motility consists of extension and retraction movements to push
cells in media, by means of type IV pili [93]. In addition to motility, these pili are also responsible for
biofilm formation and gene transfer [94]. In A. baumannii, a model of Caenorhabditis elegans infection
showed higher virulence due to motility [95]. Investigations comparing blood isolates of A. baumannii
to sputum isolates found that the former isolates were more motile, probably indicating a higher
survival advantage in blood [96].
In addition to twitching motility, some isolates of A. baumannii move on living and non-living
surfaces without relying on flagella by another mode of motility called surface-associated motility [97].
This type of motility also requires type IV pili, quorum sensing, lipo-oligosaccahride production,
and 1,3-diaminopropane, which mediates signaling needed for impacting surface-associated motility
by quorum sensing [90].
4.7. Micronutrient Acquisition Systems

A major factor contributing to A. baumannii persistence as a nosocomial pathogen is its ability to
capture host nutrients, including iron, manganese, and zinc, thus adapting to metal-limited environment
imposed by the host [98]. The main mechanism used by A. baumannii for capturing iron involves five
clusters of high-affinity iron-chelating molecules known as siderophores. In addition, the organism
possesses transporters and receptors for direct iron uptake such as FecA and FecI, which allow the
utilization of heme [99]. Models of iron transporter damage have shown to reduce virulence by
decreasing biofilm production and resistance to oxidative stress [100].
Moreover, A. baumannii relies on a high-capacity zinc scavenging system, consisting of ZnuABC
transporter and ZigA GTPase; ZnuABC assures intracellular zinc uptake, while ZigA is responsible for
zinc metabolism [101,102]. As such, A. baumannii circumvents calprotectin, an immune system protein,
that innately complexes zinc, manganese, and divalent metal ions, thus inhibiting bacterial growth. In a
murine pneumonia model, zigA mutants with depleted zinc availability had less systemic dissemination
from the lungs following infection [102]. Although mechanisms employed by A. baumannii to overcome
manganese limitation are less understood, it is postulated that a transporter belonging to the family of
resistance-associated macrophage protein (NRAMP) facilitates manganese accumulation and growth
in presence of calprotectin [103].
4.8. Protein Secretion Systems

In A. baumannii, secretion of proteins from cell surface structures allows the pathogen’s
interaction with environment and hosts, and hence represents attractive targets for treatment [104,105].
The trimeric autotransporter (Ata) was the first secretion system described in A. baumannii. Ata mediates
attachment to human matrix components, particularly collagen, and it is also implicated in biofilm
formation/maintenance and virulence [104]. A. baumannii also uses a type II secretion system (T2SS) to
export multiple effector proteins. In this two-step secretion process, the general secretory pathway
(Sec) or the Twin-arginine (Tat) system deliver proteins with an N-terminal secretion signal across the
pathogen’s inner membrane. Next, the secretion signal is removed, and T2SS machinery secretes folded
proteins to outside of the cell [106]. T2SS effectors include CpaA, LipA, and LipH, where LipA and LipH
are lipases that are essential for utilization of exogeneous lipids, and CpaA is a metallo-endopeptidase
that degrades fibrinogen and factor V in a zinc-dependent mechanism, negatively influencing blood
clotting pathways [107].
Like many Gram-negative bacteria, A. baumannii encodes type VI secretion system (T6SS),
a multi-component secretion machine capable of injecting protein toxins into other bacteria in a
contact-dependent manner, thus making it important in polymicrobial infections [108]. A single,
conserved, genetic locus encodes 13 core structural proteins of this system, while additional, accessory,
or regulatory elements may co-exist. Assembled T6SS system contracts to allow release of the effector
protein, which typically targets other bacteria without self-intoxication [104]. In A. baumannii, T6SS
may attack other bacteria, where it produces toxins like nucleases, peptidoglycan hydrolases, or
cell-membrane active toxins [109]. Interestingly, clinical isolates with active T6SS are isolated at
higher frequencies from immunocompromised patients, suggestive of competitive advantage against
concomitant pathogens [110].
4.9. Others
Although tangible progress was accomplished in A. baumannii pathogenesis studies, emerging
areas are still under in-depth investigation. Among these, outer membrane vesicles, long recognized to
protect bacteria against host innate immunity, are being studied for their ability to provide mechanisms
for secretion of virulence factors in A. baumannii [99]. Possibilities also exist that A. baumannii may
acquire a toxin-like virulence factor like other human pathogens such as Vibrio cholerae [111]. Indeed,
ongoing research on molecular mechanisms utilized by this pathogen for survival within the host and
adaptation to environmental stress could uncover additional important pathogenesis features.
5. Mechanisms of Antibiotic Resistance in A. baumannii

The increased antimicrobial resistance in A. baumannii and the occurrence of strains resistant to
virtually all available drugs is quite alarming [4]. Intrinsically resistant to a number of commonly used
antibiotics, such as aminopenicillins, first- and second-generation cephalosporins, A. baumannii has a
quite notable ability to acquire resistance to numerous other agents and thus swiftly respond to changes
in environmental pressure [2]. The current guidelines of treatment of infections by A. baumannii are
seriously affected by such resistance inclination, rendering options of chemotherapy rather limited [36].
For susceptible organisms, first-line therapy consists of a carbapenem, such as imipenem-cilastatin,
meropenem, or doripenem [112], where imipenem was historically considered the gold standard
for management of VAP caused by this organism [113]. The clinical cure rates with imipenem for
A. baumannii-induced VAP range from 57% to 83%. Because isolates susceptible to imipenem may be
resistant to meropenem and vice versa, it is advisable to test susceptibility to the specific carbapenem
prior to its clinical use [114]. Nevertheless, as explained shortly, carbapenem resistance rates for
A. baumannii have been rising dramatically worldwide, rendering the antibiotic armamentarium more
restricted, and clinical practice is shifted towards alternative agents [36]. Of these, colistin (polymyxin
E) and polymyxin B are being used to treat A. baumannii VAP, bacteremia and meningitis [113]. A major
Antibiotics 2020, 9, 119 10 of 29
limitation to colistin is high rates of nephrotoxicity and neurotoxicity, as well as poor penetration
into the lung tissue, incumbering its utility [115]. Another alternative agent is minocycline, where
successful clinical and microbiologic outcomes were reported for patients with A. baumannii VAP as
well as skin and soft tissue infections [116]. Tigecycline, an alternative antibiotic for MRD and XDR
strains of A. baumannii, has been used with variable success rates [117,118]. Despite reasonable in vitro
activity of this agent against A. baumannii, clinical data remain limited. Specifically, in clinical trials
with A. bauamnnii VAP and bacteremia, patient outcomes with tigecycline have been inferior to other
β
agents [119]. An interesting alternative to both tetracyclines, minocycline and tigecycline, may be the
β-lactamase inhibitor, sulbactam, which has direct antimicrobial activity against A. bauamnnii, via its
intrinsic affinity for A. baumannii penicillin-binding proteins [36]. A major disadvantage of sulbactam is
that it is only available in combination with ampicillin in the United States, besides emerging resistance,
warranting further investigations into the clinical utility of this agent [120].
Combination therapy is frequently used in A. baumannii infections as a strategy to increase antibiotic
coverage before drug susceptibility testing results are known, to decrease the risk of resistance, and to
improve patient outcomes. However, there are no definitive clinical data to support its use for these
purposes, and results from human trials are limited [112]. For example, therapy with polymyxin B plus
another agent (imipenem, meropenem, rifampin, ampicillin-sulbactam, or others) was associated with
a lower mortality rate than with polymyxin B monotherapy [121]. A randomized, multicenter trial
done on patients with XDR A. baumannii infections treated with colistin and rifampin versus colistin
alone, showed superior microbial eradication in patients randomized to the combination arm, but no
difference in mortality [122]. Other combination regimens suggest increased efficacy of sulbactam
with cefepime, meropenem, imipenem, amikacin, or rifampin [123]. Alternative combinations include
colistin-tigecycline and colistin-carbapenem therapy, with the latter perhaps the most supported [36],
and have been recommended in several trials [124–126]. Furthermore, a recent investigation has
highlighted a remarkable synergistic interaction between colistin and vancomycin [127].
A clear consensus regarding the most appropriate combination therapy for resistant A. baumannii
infections remains to be established, pending more comprehensive clinical studies. Until these become
accessible, and until novel antimicrobial entities, bacteriophages, or antimicrobial peptides, which are
under thorough scientific investigation, become established, resistance of A. bauamnnii to contemporary
therapies will escalate. Figure 3 and Table 1 summarize the antibiotic resistance mechanisms in
A. baumannii; an elaboration of these mechanisms with literature citing them is presented below.
Figure 3. Diagram of various resistance mechanisms of Acinetobacter baumannii to antimicrobial agents.

Antibiotic modifying enzymes, efflux pumps, porins, drug targets, and the affected antibiotics by each
resistance mechanism are shown. AMEs = Aminoglycoside modifying enzymes; AmpC = Ambler
class C cephalosporinases; ESBLs = Extended-spectrum β-lactamases;β MBLs = Metallo-β-lactamases; β
LPS = Lipopolysaccharide; PBP = Penicillin binding protein.
Antibiotics 2020, 9, 119 11 of 29
5.1. β-lactams
The most prevalent mechanism of resistance of A. baumannii to β-lactams is enzymatic hydrolysis
by β-lactamases; all of the four Ambler classes of these enzymes have been described in this organism,
in addition to nonenzymatic pathways.
5.1.1. Ambler Class A Enzymes

Class A β-lactamases are serine-dependent enzymes inhibited by clavulanate or tazobactam.
They hydrolyze all penicillins and cephalosporins with the exception of cephamycins [128]. CTX-M,
GES, PER, SCO, SHV, TEM, and VEB are among identified class A β-lactamases in A. baumannii [129–132].
While some of these, like SCO-1 and TEM-1, are narrow-spectrum, others like CARB-10, CTX-M-2,
CTX-M-15, GES-14, PER-1, PER-7, and SHV-5 are extended spectrum β-lactamases (ESBLs) [133,134].
Some GES enzymes with carbapenem-hydrolyzing activity, such as GES-11, have been detected in
A. baumannii [135,136].
In 2010, Robledo et al. reported, for the first time, Ambler class A Klebsiella pneumoniae
carbapenemase (KPC)-5 in MDR A. baumannii from Puerto Rico [137]. Additional reports described
KPC-3 in A. baumannii a Portugese University hospital [138], and both KPC-2 and KPC-3 in isolates
from Brazil [139]. In a recent meta-analysis about A. baumannii in burn injury patients, the prevalence
of KPC was over 16% [140]. Carriers of a KPC variants are usually MDR microorganism, and standard
medical treatment becomes ineffective with high mortality rates [139]. The true prevalence of KPC and
its probable association with other resistance determinants should be investigated carefully, especially
with reports of already globally disseminated A. baumannii ST2 that carries blaKPC [141].
5.1.2. Ambler Class B Enzymes

These are zinc-dependent metallo-β-lactamases (MBLs), that strongly hydrolyze all β-lactams,
including carbapenems, but not aztreonam [142], and are inhibited by metal chelators like EDTA
and dipicolinic acid [128].The most concerning among MBLs is NDM-1, with carbapenem-resistant
A. baumannii producing NDM-1 being identified in 2011 in China [143]. Additional reports of NDM-1
in A. baumannii have accumulated from Tunisia [144], Iran [145], Lebanon [146], and Saudi Arabia [147].
Apart from NDM, VIM [148], GIM [149], SIM [150], and IMP [151,152], including a new allelic variant,
IMP-55 [153] were reported.
The majority of acquired MBL genes in A. baumannii lie on class 1 integrons, which simultaneously
harbor other resistance genes, like aminoglycoside resistance [154]. Such strains are significantly more
resistant than strains without integrons, and, clinically, this implies that use of one antibiotic can result
in overexpressed resistance to other antibiotics, especially with genetic location of integrons on mobile
elements like plasmids or transposons, making them easily transferrable [155].
5.1.3. Ambler Class C Enzymes

Also known as Acinetobacter-derived cephalosporinases (ADCs), chromosomally encoded AmpC
cephalosporinases are intrinsic to all A. baumannii strains [155]. They mediate cephamycin (cefoxitin
and cefotetan), cephalosporin, penicillin, and β-lactamase inhibitor combinations resistance, but are not
affected by β-lactamase inhibitors like clavulanate and sulbactam [156]. Unlike other Gram-negative
bacteria, A. baumannii does not induce expression of AmpCs. Overexpression is usually mediated
by inserting ISAba1 before AmpC genes, enhancing A. baumannii resistance to extended-spectrum
cephalosporins [157]. Cefepime and carbapenems appear to be stable in the presence of these
enzymes [155]. Whole-genome sequencing approaches are allowing detection of new AmpC alleles
like AmpC-69, AmpC-70, and AmpC-71 [158]; the new AmpC allelic variant encoded by blaADC-196
was also recently identified in a clinical A. baumannii isolate from China [159].
Antibiotics 2020, 9, 119 12 of 29
5.1.4. Ambler Class D Enzymes

β-lactamases of class D, or the oxacillinases (OXAs), are serine-dependent and commonly
hydrolyze oxacillin much faster than benzylpenicillin, hence the name [156]. In various bacteria, over
400 OXA-type enzymes are already known, of which many are carbapenemases [133]. A. baumannii
isolates harboring plasmid-encoded OXA-23, OXA-24/40, OXA-58, OXA-143, and OXA-235 families
have appeared from the 1980s onwards; chromosomal loci encoding some of these enzymes were also
identified [20,160–163].
The first isolation of a carbapenem-hydrolyzing class D oxacillinase from A. baumannii dates
back to 1985, where it was isolated from blood culture of a Scottish patient, and termed ARI-1 [164],
which is now referred to as OXA-23 [165]. This enzyme is currently disseminated worldwide [166],
and the insertion sequence, ISAba1, in the blaOXA-23 promoter is associated with overexpression [21].
A. baumannii naturally produces chromosomally encoded OXA-51-group carbapenemase at a low level,
and acquisition of a strong promoter by ISAba1, analogous to the case with ADCs, upstream of the
OXA-51-group gene may lead to elevation of carbapenem MICs [167].
It is worth mentioning that OXA-23 enzymes have been identified in many areas of the world
in concurrence with other carbapenemases in A. baumannii clinical isolates. For instance, OXA-23
co-exists with GES-11 in reports from Lebanon [136] and Kuwait [168], with NDM-1 in reports from
India [169], and with OXA-58 in reports from Tunisia [170]. In a study from Thailand, a rare, worrisome
case of A. baumannii exhibited OXA-23, VIM-2, and NDM-1 [171], highlighting the versatility of
carbapenemases that can be harbored simultaneously by this organism.
5.1.5. Nonenzymatic β-lactam Resistance Mechanisms

Apart from β-lactamases, β-lactam resistance in A. baumannii is additionally ascribed to
nonenzymatic mechanisms, perhaps less well elucidated than enzymatic hydrolysis, but mainly
including changes in outer membrane proteins and multidrug efflux pumps [155]. The loss of the
29-kDa outer membrane porin, CarO, was associated with imipenem and meropenem resistance [172].
A recent study from Egypt revealed that ISAba1 has been inserted in carO gene leading to interruption
of its expression [173]. A report about an insertion sequence disrupting the gene encoding the penicillin
binding protein PBP6b (also known as dacD) was identified in an endemic carbapenem-resistant clone
in a Spanish hospital [174]. Additionally, a collective set of changes involving disruptions in carO
and dacD, as well as carbapenemase production, developed resistance to carbapenems among clinical
isolates of A. baumannii [175]. The role of other porins like OmpA, Omp33, OprB, Omp25, OprC, OprD,
and OmpW is also reported [176].
Multi-drug efflux systems play a major role in β-lactam resistance in A. baumannii.
The resistance-nodulation-division (RND) family-type pump AdeABC is the best studied and has
a broad substrate range including β-lactams, aminoglycosides, erythromycin, chloramphenicol,
tetracyclines, fluoroquinolones, and trimethoprim [155]. AdeABC has a three-component structure:
Outer membrane protein (adeC), multidrug transporter (adeB), and membrane fusion protein (adeA) [177].
This pump is chromosomally encoded and regulated by a TC system with a sensor kinase (AdeS) and
an associated response regulator (AdeR) [178]. Either point mutations or insertion of ISAba1 sequence
in adeS gene leads to overexpression of AdeABC [133]. In a Chinese report, high expression of AdeABC
in A. baumannii was closely associated with meropenem resistance. The upregulation of adeA and adeB
expression was not due to gene mutations in the regulatory genesadeS and adeR, suggesting possible
involvement of other pathways for efflux pump overexpression [179].
5.2. Tetracyclines and Glycylcyclines

Similar to other Gram-negative organisms, tetracycline resistance in A. baumannii occurs primarily
via energy-dependent efflux pumps, with a lesser extent of resistance attributed to ribosomal protection
mechanisms through encoding proteins that shield bacterial ribosomes [180]. Tetracycline efflux
Antibiotics 2020, 9, 119 13 of 29
pumps of A. baumannii fall into two categories: RND pumps, which are nonspecific, constitutive
pumps, and Tet efflux pumps with TetA conferring resistance to tetracycline but not minocycline or
doxycycline and TetB resulting in resistance to minocycline and tetracycline, tigecycline remaining
unaffected [181]. The general structure of RND pumps includes three parts, namely, AdeA, AdeB,
and AdeC in A. baumannii. These respectively encode membrane fusion, multidrug transporter,
and outer membrane pump elements [178]. Gene disruption analysis proved that RND pumps can
eject tetracyclines, elevating MICs for tigecyline, minocycline, and tetracycline [182]. Other RND
pumps like AdeIJK exist but may play a less profound role on tetracycline efflux and can be synergistic
with AdeABC [183].
According to studies from many countries, overexpression of the efflux pumps AdeABC and
AcrAB-TolC efflux systems was observed in clinical tigecycline-resistant isolates [184–186]; this is
increasingly affecting utility of this modified tetracycline in treatment. Tigecycline has broader spectrum
of activity compared to earlier tetracyclines, has good tissue penetration, and is stable against many
tetracycline resistance mechanisms including Tet efflux pumps, as well as against ribosomal protection,
such as Tet(O) and Tet(M) [187]. Control of tigecycline usage should be considered to reduce emergence
of resistance.
Resistance to minocycline in A. baumannii is rare and has been attributed to tetM, a ribosomal
protection gene [181]. This gene possesses almost 100% homology to S. aureus gene, and may represent
transfer of resistance mechanisms between the two pathogens [188]. Because tetM encodes a GTPase
analogous to the elongation factors EF-G and EF-Tu, it can mediate tetracycline release from bacterial
ribosome by a GTP-dependent mechanism, through competition with EF-G for an overlapping binding
site. By dissociation of tetracycline from its ribosomal binding site, tetM enables translation to continue
in the presence of tetracycline [189]. Recent evidence shows that tetM is encoded by A. baumannii
isolated from wastewater treatment plants [190] and animal culture ponds [191], indicating extensive
dissemination; the assessment of such resistance pools is critical not only for clinical significance, but
also for environmental protection.
5.3. Fluoroquinolones
The emergence of resistance to fluoroquinolones in A. baumannii results from mutations of the
fluoroquinolone target enzymes, DNA gyrase and DNA topoisomerase IV, respectively encoded by the
genes gyrA and parC. [192]. These mutations mainly affect the fluoroquinolone-resistance determining
regions (QRDRs) of the target enzymes, with common amino acid substitutions being Ser 83 and
Gly 81 within gyrA, and Ser 80 and Glu 84 within parC. [193]. Such mutations decrease affinity of
fluoroquinolones to the enzyme-DNA complex. Clinically significant resistance to fluoroquinolones
may be achieved with only a single mutation in gyrA; however, double amino acid of both gyrA and parC
produce augmented resistance compared to single ones [194]. There has not been evidence of mutations
in parC without a concurrent mutation in gyrA, which suggests that DNA topisomerase IV could be a
complementary target for fluoroquinolones [193]. So far, plasmid-mediated fluoroquinolones resistance
genes like qnrA, qnrB, and qnrS have not been identified in epidemiologic studies of A. baumannii.
Moreover, moderate level fluoroquinolone resistance in A. baumannii may result from
chromosomal efflux pumps [81]. Efflux pump inhibitors can reverse multidrug resistant phenotype
of A. baumannii [194]. Mutations of a two-step regulator (AdeR) and sensor (AdeS) of the previously
mentioned AdeABC efflux pump belonging to RND family of pumps resulted in higher fluoroquinolone
efflux [192]. Finally, quinolones are the principle substrates of the efflux pump AbeM, resulting in
clinically significant MIC changes for ciprofloxacin and norfloxacin [195]. It is worth mentioning
that AbeM is a hydrogen-ion-coupled member of the multidrug and toxic compound extrusion
(MATE) family.
Antibiotics 2020, 9, 119 14 of 29
5.4. Aminoglycosides
Aminoglycoside resistance in A. baumannii results from production of aminoglycoside-modifying
enzymes (AMEs), which can be categorized into various groups with different chemical actions,
including acetyltransferases, adenyltransferases, and phosphotransferases [196]. Such AMEs alter
corresponding functional groups on aminoglycosides, weakening the binding capacity of these
antibiotics at their ribosomal target sites. AMEs are often found within class 1 integrons and can be
located on either plasmids or chromosomes [197]. The action of AMEs is selective, whereby they
differently affect various aminoglycoside molecules. For instance, A. baumannii phosphotransferases
can make many aminoglycosides, including amikacin, inactive. Gentamicin and tobramycin retain
activity because of their inability to accept phosphate secondary to a lack of 3′ -hydroxyl groups [198].
A. baumannii isolates may produce a combination of AMEs, as in a PDR A. baumannii strain described
in China and carrying four AMEs [199]. Among others, AAC(3)-Ia, ANT(2’)-Ia, and ANT(3”)-Ia are
variants of AMEs described in A. baumannii [186,200,201].
Another resistance mechanism to aminoglycosides is the production of 16S rRNA methylase genes
armA, rmtA, rmtB, rmtC, and rmtD, which alter target binding site for aminoglycosides within the 30S
ribosomal subunit. Unlike AMEs, methylases induce high-level resistance across all clinically useful
aminoglycosides, including gentamicin, tobramycin, and amikacin [198]. The armA gene is found
among other Gram-negative organisms, is plasmid-borne, and lies within a transposon (Tn1548) [202].
Although AMEs remain the principle aminoglycoside resistance mechanism in A. baumannii, these
antibiotics are also subject to efflux pump ejection outside the cell. Gentamicin is subject to effective
efflux by AdeABC and AbeM pumps, while these two pumps are less efficient in extruding the more
hydrophilic aminoglycosides, amikacin and kanamycin [176,203].
5.5. Macrolides
While azithromycin shows variable activity against some A. baumannii isolates, this does not
really appear significant for clarithromycin and erythromycin [203]. There are only scarce reports
in literature on successful treatment of infections caused by A. baumannii with macrolides; however,
A. baumannii with a mutant AbeS small multidrug resistance (SMR) pump exhibits erythromycin
and chloramphenicol resistance [204]. Recently, an investigation from Japan [205] proved that the
MacA-MacB-TolC tripartite complex transmembrane machine of A. baumannii that spans both the
inner and outer membranes exists as a unique type of transporter. Macrolides, virulence determinants,
peptides, and cell envelop elements appear to be important substrates of this transporter.
5.6. Polymyxins
Polymyxin E, also known as colistin, is an old antibiotic belonging to the polymyxin family, first
introduced in the 1950s; owing to its harmful effects on renal function, its use was banned by many
countries [206]. Nevertheless, the rapid emergence of resistance in A. baumannii to multiple antibiotics,
including carbapenems, has revived interest in the use of colistin. Currently, resistance to this latter
antibiotic in A. bauamannii is on the rise [207].
Primary colistin resistance mechanisms in A. baumannii are chromosomally encoded, and involve
(i) phosphoethanolamine (PetN) addition to lipid A of the outer membrane altering its structure,
(ii) mutation of genes needed for lipid A synthesis leading to its complete loss, (iii) of outer membrane
low expression of proteins needed for outer membrane stability, and (iv) deficient expression of LPS
synthesis cofactors [207]. Polymyxins are cationic amphipathic compounds, and initially interact with
the negatively charged lipid A component of LPS. Controlled addition of positively charged residues
such as PetNt to LPS reduces negative charge on bacterial surface and therefore limits interaction
between the polymyxin and the LPS [208]. The expression of PetN transferases is regulated by the
concerted action of TS systems [209]. Colistin resistance in A. baumannii clinical isolates is associated
with alterations in the pmrCAB operon. The pmrC gene codes for a PetN transferase, and pmrA and
Antibiotics 2020, 9, 119 15 of 29
pmrB code for TS system. Mutations in the PmrAB TS system induce overexpression of pmrC, leading to
modification of lipid A with PetN and colistin resistance [210]. Uniquely, A. baumannii strains can also
become highly resistant to polymyxins via spontaneous mutations in lipid A biosynthesis such that
they produce no LPS or lipid A. If the biosynthetic lipid A genes, lpxA, lpxC, or lpxD, become completely
inactive, LPS is lost, elevating colistin MIC due to lack of LPS interaction with this antibiotic [211].
Recently, additional genes (lpsB, lptD, and vacJ) were shown to contribute to polymyxins resistance
in A. baumannii. These genes reduce fluidity and increase osmotic resistance of the outer membrane.
In overexpression mutations of these genes, polymyxin resistance in A. baumannii occurs [212].
The levels of biotin are essential for susceptibility to polymyxins in A. baumannii. Biotin is a co-factor
of lipid metabolism, involved in a rate-limiting step in fatty acid synthesis. Accordingly, high levels
of biotin promote increased lipid A synthesis, with higher sensitivity to colistin. On the other hand,
mutations in genes needed for biotin synthesis reduces effectiveness of colistin [212]. Hood and
colleagues showed that removal of a particular locus of lpsB, which is involved in biotin biosynthesis
can result in colistin resistance in A. baumannii [213].
Resistance to colistin in A. baumannii was originally chromosomal, which limits its rapid
distribution and dissemination [207]. However, the plasmid-borne mcr-1 gene was identified in
Escherichia coli of animal, human, and environmental origin from China in 2015 [214]. Subsequently,
mcr-1.2, mcr-2, mcr-3, mcr-4, and mcr-5 variants were also identified [215]. Diverse plasmids with
mcr genes are nowadays described in Enterobacteriaceae from many countries. This gene encodes
a PetN transferase resulting in polymyxin resistance. Despite that, mcr has not been described in
A. baumannii until recently in reports from Pakistan [206] and Brazil [216], probably highlighting the
high tendency for spread and stressing the need to understand the actual status of global colistin
resistance in this pathogen.
Antibiotics 2020, 9, 119 16 of 29
Table 1. Important resistance determinants in Acinetobacter baumannii showing possible enzymes/target modifications/permeability lesions.
Enzyme/target/
Antibiotic Resistance Mechanism Example Reference
Permeability Defect
ESBLs of the families TEM, SHV, CTX-M, PER and VEB [129–132]
SCO-1 (narrow spectrum) [134]
Carbapenem-hydrolyzing ESBL of GES-type (GES-11) [135,136]
Ambler class A
KPC-2 [139]
KPC-3 [138,139]
KPC-5 [137]
NDM [143–147]
VIM [148]
β-lactamases GIM [149]
Ambler class B
β-lactams SIM [150]
IMP [151–153]
Ambler class C AmpC-69, AmpC-70, AmpC-71, and ADC-196 [2,157,158]
OXA-23-like [20,136,164,165,167,170]
OXA24/40-like [159]
OXA-51-like [20,166]
Ambler class D
OXA-58-like [169]
OXA-143-like [161]
OXA-235-like [162]
Outer membrane porin CarO [171,172,174]

Permeability lesions
downregulation OmpA, Omp33, OprB, Omp25, OprC, OprD, and OmpW [175]
Efflux pump overactivity RND pump AdeABC [2,176,177]
Target mutation PBP PBP6b (dacD) [173,174]
Antibiotics 2020, 9, 119 17 of 29
Table 1. Cont.
Enzyme/target/
Antibiotic Resistance Mechanism Example Reference
Permeability Defect
RND pump AdeABC, AdeIJK, and AcrAB-TolC [179–185]
Efflux pump overactivity
Tertacyclines Tet pump TetA and TetB [180]
Ribosomal protection Tetracycline dissociation from ribosome Tet(O) and Tet(M) [180,186–188]
DNA gyrase GyrA [191,192]
Target mutation
DNA topoisomerase IV ParC [191,192]
Fluoroquinolones
RND pump AdeABC [81,191]
Efflux pump overactivity
MATE family AbeM [194]
AAC(3)-Ia [185]
AAC(3′ )-Ia [200]
Drug inactivating enzymes Aminoglycoside modifying enzymes
ANT(2′ )-Ia [200]
Aminoglycosides
ANT(3”)-Ia [199]
Target mutation 16sRNA methylase genes armA, rmtA, rmtB, rmtC, and rmtD [197,201]
Efflux pump overactivity RND pumps AdeABC [175,202]
Macrolides Efflux pump overactivity SMR pump AbeS [204]
PmrC [208–210]
Lipid A modification by PetN transferase MCR-1 [214]
MCR-4 [215,216]
Polymyxins Target mutation
Lack of lipid A biosynthesis LpxA, LpxC, or LpxD [211]
Decreased stability of outer membrane LpsB, LptD, and VacJ [212]
Reduced biotin synthesis LpsB [207,212,213]
ESBLs = Extended-spectrum β-lactamase; PBP = Penicillin binding protein; RND = resistance-nodulation-division; MATE = multidrug and toxic compound extrusion; SMR = small
multidrug resistance; PetN = phosphoethanolamine.
Antibiotics 2020, 9, 119 18 of 29
6. Conclusions
A. baumannii has developed three basic properties to perfectly adapt to current healthcare settings:
(i) Ability to colonize skin, mucous membranes, and devices and survive in the hospital environment;
(ii) ability to express multiple virulence features; and (iii) extensive resistance to antimicrobial
agents through enzymatic modification of antibiotics, target gene mutation, altered outer membrane
permeability, and upregulated multidrug efflux pumps. With rapid increase in studies addressing the
entire armamentarium of virulence determinants and resistance pathways possessed by this superbug,
its complex influences on human health are gradually uncovered. Indeed, thorough investigations will
reveal additional knowledge about this staggering pathogen, and the future holds promise for better
insights into its machineries through novel research directions.
Author Contributions: D.H.H. conceptualized and wrote the first draft of this review. C.A.M. was in charge of
revision and editing. All authors have read and agreed to the published version of the manuscript.
Funding: The APC was funded by Zayed University.
Conflicts of Interest: The authors declare no conflict of interest.
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5.

Insights into Acinetobacter

Carole Ayoub Moubareck and Dalal Hammoudi Halat

Keywords: Acinetobacter baumannii; multidrug resistance; virulence factors; antibiotics; pathogenesis

Antibiotics 2020, 9, 119; doi:10.3390/antibiotics9030119 www.mdpi.com/journal/antibiotics

2. Taxonomy and Microbiological Properties of Acinetobacter baumannii

3. Associated Infections and Clinical Impact of A. baumannii

3.1. Respiratory Infections

3.2. Bloodstream Infections

3.3. Skin and Soft Tissue Infections

3.4. Urinary Tract Infections

4. A. baumannii Virulence Factors

Figure 2. An illustration of virulence determinants possessed by Acinetobacter baumannii. The function

4.1. Outer Membrane Proteins (Porins)

4.2. Cell Envelope Factors (LPS and Capsule)

4.5. Biofilm Production and Quorum Sensing

4.7. Micronutrient Acquisition Systems

4.8. Protein Secretion Systems

5. Mechanisms of Antibiotic Resistance in A. baumannii

Figure 3. Diagram of various resistance mechanisms of Acinetobacter baumannii to antimicrobial agents.

5.1.1. Ambler Class A Enzymes

5.1.2. Ambler Class B Enzymes

5.1.3. Ambler Class C Enzymes

5.1.4. Ambler Class D Enzymes

5.1.5. Nonenzymatic β-lactam Resistance Mechanisms

5.2. Tetracyclines and Glycylcyclines

Outer membrane porin CarO [171,172,174]

113. Garnacho-Montero, J.; Ortiz-Leyba, C.; Jiménez-Jiménez, F.J.; Barrero-Almodóvar, A.E.;

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