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Letters in Drug Design & Discovery, 2021, 18, 000-000 1

RESEARCH ARTICLE

Anti-evolution Drugs: A New Paradigm to Combat Drug Resistance

Ramalingam Peraman1, Santhivardhan Chinni1,*, Sathish Kumar Sure1, Vinay Kumar kutagulla1,
Muthukumaran Peraman3, Azger VN2 and Padmanabha Reddy Y1

1
RERDS-Centre for Pharmaceutical Research, Raghavendra Institute of Pharmaceutical Education and Research (Rip-
er)-Autonomous, Anantapur, AP, India -515721; 2ICMR-National Institute for Research in Tuberculosis, Chennai, TN,
India – 600031; 3Kumaraguru College of Technology, Coimbatore, Tamil Nadu, India-641049

Abstract: Drug resistance confronts chemotherapy of neoplasm and microbial infections. A vast
array of molecular mechanisms was implicated in drug resistance, including generation of drug ef-
ARTICLE HISTORY flux transporters, mutation of drug targets, and alteration of drug metabolism. With the alarming rate
of increase in drug resistance, pathogens are bolstering in such a way that many new drugs face effi-
Received: December 08, 2020 cacy problems within a short span of entry into the market. Evolution is the driving force towards the
Revised: April 13, 2021
development of drug resistance. By adopting the modern genomic and functionomic analytical tech-

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Accepted: June 08, 2021
niques, scientists have now identified novel genes and signalling proteins involved in the evolution

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of drug resistance in microorganisms. Given the current knowledge of bacterial evolution, antibiotic

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DOI:

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10.2174/1570180818666210804142612   drug discovery is ready for a paradigm shift to explore the newer ways to tackle drug resistance. The
article discusses such recent developments and reviews their merits and demerits in an attempt to

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envisage the findings in this new domain of medicine.
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Keywords: Mfd, competence blockers, Hsp90, APOBEC, MPS1, drug resistance,·anti-evolution.
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1. INTRODUCTION new antibiotics is not yet promising and demands alternative

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solutions [2]. At this juncture, there is a need for new antibi-

Many pathogenic microorganisms have been developing
otics suitable for combating resistant pathogens. However,
drug resistance to the existing classes of antimicrobial drugs.
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researchers keep reporting about the drug-resistant pathogen-

The spontaneous mutation of genes in microbes over a peri-
ic microbes and their ability to develop resistance to all ex-
od of time resulted in an era of antibiotic crisis, which is not
isting drugs, including newly introduced antibiotics. For ex-
only limited to bacterial infections but also tuberculosis, ma-
A

ample, Mycobacterium tuberculosis (Mtb) can mutate

laria, viral, and fungal infections. Thus, the new generation faster to generate more challenging strains that are resistant
antimicrobial drugs need to target the microbes with novel
to newly developed drugs [4]. Still, there are ways to attenu-
mechanisms to curtail the antimicrobial resistance (AMR)
ate the emergence of drug resistance.
[1]. AMR is responsible for 700,000 deaths annually, and it
or

is also predicted that the mortality rate could reach up to 10 Evolutionary changes in the microbial genome are the
million by 2050 if no appropriate measures are taken [2]. A driving force towards the development of drug resistance in
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list of "priority pathogens" published by WHO [3] exposed microorganisms. It adapts the cells to a new environment and
the jeopardy associated with 12 families of life-threatening implicates replicative immortality. More commonly, micro-
multi-drug-resistant bacteria, especially the gram-negative organism develops drug resistance through the building of
species that are extremely resistant to multiple antibiotics. reinforced cell walls and efflux pump mechanisms. Until
Some of the most typical families of bacteria, such as Aci- recently, the drug discovery is targeted to inhibit the efflux
netobacter, Pseudomonas, Klebsiella, E. coli, Serratia, and pumps or perforation of cell walls, which eventually failed.
Proteus species are posing severe challenges to the medical After discovering certain critical mechanisms involved in the
community as they are the common cause of fatality due to evolution of resistance, the research is now taking a para-
nosocomial and ventilator acquired infections. The drug- digm shift. Thus, now the focus is not only to kill but also to
resistant mechanisms of these organisms could often be freeze the evolution of microbes to curb the development of
transmitted via genetic material, thus allowing others to be- multi-drug resistance.
come resistant too. Although the search for unconventional
antimicrobial drugs remains a top priority, the pipeline for 2. ANTI-EVOLUTION DRUGS FOR MICROBIAL
INFECTIONS
*Address correspondence to this author at the RERDS-Centre for Pharma- Scientists have recently found anti-evolution mechanisms
ceutical Research, Raghavendra Institute of Pharmaceutical Education and
Research (Riper)-Autonomous, Anantapur, AP, India -515721;
which could prevent the pathogenic microbes from ratchet-
E-mail: [email protected] ing up their shields against the new drugs. Anti-evolution

1570-1808/21 $65.00+.00 ©2021 Bentham Science Publishers

2 Letters in Drug Design & Discovery, 2021, Vol. 18, No. 0 Peraman et al.

drugs are adjuvants that require concomitant administration monia. As a result, 46 drugs belonging to the class of anti-
with antimicrobial drugs. An antibiotic kills or inhibits the psychotics, antimicrobials, and antimalarial drugs were iden-
proliferation of cells, whereas an anti-evolution drug freezes tified to interfere with the mutation process at low doses.
the microorganisms from evolving and makes them vulnera- From these, pimozide, triclosan, and proguanil were identi-
ble to immune attack. fied as potent blockers of competence (COM blockers) at 16-
32 times lower than the MIC. The concentrations of drugs
3. TARGETING MFD used to block the competence of microorganisms were much
lower than the concentration required for inhibiting the
The ‘mutation frequency decline (Mfd) protein’ is a growth. As the COM-blockers act at the sub-inhibitory con-
DNA translocase, a coupling factor for transcription repair centrations, they might exert a lower tendency to create drug
and exhibits pro-mutagenic functions. It plays a crucial role resistance. A distinct feature of COM-blockers is that they
in DNA repair and is critical for acquiring multiple muta- do not compromise the antibacterial activity when coadmin-
tions in bacteria [5]. Recently, a group of scientists from the istered with antibiotics at their effective concentrations.
University of Washington identified that Mfd is an evolva- Therefore, they can be used as adjuvants to address antibiotic
bility factor involved in developing antibiotic resistance. resistance (Fig. 2).
They experimented with the inhibition of Mfd in bacterial
colonies of Mtb and Salmonella typhimurium to devel-
5. TARGETING ROS
op a new strategy in decelerating the mutations and evolu-
tion of microorganisms. The resultant colonies have a re- In addition to the antimicrobial action, antibiotics can
duced capacity to mutate and are highly susceptible to anti- also expedite the genetic variability in bacteria. Conversely,
biotics. A comparative experiment on wild-type and Mfd- the probability of acquiring drug resistance is intensified as a
deficient Mtb demonstrated a significant difference in the result of genetic variability. Fudging the physiological re-

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capacity to develop resistance to rifampicin (Fig. 1). sponses that influence such genetic changes is a way to im-

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pede the resistance to drugs. Inhibition of topoisomerase II

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Further, Mfd-deficient bacterial strains were 1,000-fold

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(TPI2) can induce the SOS response, in turn upregulate the
more sensitive to antibiotics than wild-type. Supporting this DNA translesion synthesis (TLS) in Escherichia coli. Even-

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evidence, an initial study on S. typhimurium confirmed
tually, the SOS response generated by fluoroquinolones
the role of Mfd as a critical factor for hypermutation. In con-
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se (TPI2 inhibitors) promotes the erroneous DNA replication
trast, Mfd deficient strains failed to form hypermutator al-
mediated by TLS polymerases in the resistant strains of E.
leles [6]. However, the mechanism of Mfd in the promotion
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Coli [8, 9].

of mutagenesis and the development of drug resistance is
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unclear. However, it was postulated that Mfd induces muta- Further, fluoroquinolones have been shown to increase
genic DNA repair through a low fidelity gap-filling during the production of reactive oxygen species (ROS), an addi-
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the DNA repair process and restrains other pathways from tional mechanism of antibacterial action. ROS production is
fixing the damaged DNA. Regardless of nature, blocking the increased in the presence of destabilized iron-sulphur clus-
evolvability factors (Mfd) could revolutionize antimicrobial ters [10]. Both SOS response and ROS play a pivotal role in
therapy by reviving many antibiotics' therapeutic potentials. microbial mutagenesis triggered the emergence of drug-
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resistant mutants during treatment with fluoroquinolones.

4. TARGETING PMF AND COMPETENCE Few recent studies reported new agents for diminishing the
mutagenic effect in microbes by modulating ROS production
Antibiotics steer the spread of AMR by inducing stressful and the SOS response.
or

environmental conditions. One such mechanism behind the

development of resistance is the tendency of bacteria to pick The ROS in microbes instigates the sigma-S (sS) mediat-
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up DNA from the environment through horizontal gene ed mutagenic DNA break repair (MBR) mechanism trig-
transfer. A recent study demonstrated that drugs could block gered by dsDNA breaks because of the organism’s exposure
the bacterial competence in Streptococcus pneumonia [7]. to ciprofloxacin. Researchers found that the ROS-reducing
The study was performed in a mouse model, where drugs drug edaravone inhibits ciprofloxacin induced mutagenesis
blocked the ‘competence’ without affecting the cell growth. at a concentration of 100 µM. Edaravone reduced the ap-
This blockade prevented the bacterial strains from evolving pearance of sS-rich cells, sS-fusion protein, and ROS-rich
into drug-resistant strains. The mechanism behind this anti- cells in a microbial culture. Importantly, edaravone did not
evolution property was driven through the attenuation of affect the antibiotic activity of ciprofloxacin, which means it
proton-motive force (PMF) of bacteria. The PMF is essential removes the ROS in the sS-rich subpopulation without af-
for bacteria to produce energy, import nutrients, and shuttle fecting the potency of the antibiotic. Edaravone serves as a
cargo in and out of its body. In the resistant strains of S. prototype small molecule inhibitor of mutagenesis that could
pneumonia, PMF regulates the export of a competence stim- be concomitantly administered with ROS-inducing antibiot-
ulating peptide (CSP) that regulates the transformation ma- ics to prevent the development of sS-medicated drug re-
chinery. Accumulation of CSP outside the cell triggers the sistance [11].
horizontal transfer of antibiotic-resistant genes. Hence, upon Further, ROS mediated evolution in E. coli by ciproflox-
exposure to competence pathway inhibitors, the PMF levels acin induced mutagenesis was inhibited by ROS scavenging
were disrupted, and CSP is not pumped out. agents like thiourea and 2,2'-bipyridine [11, 12]. An E.
The researchers screened about 1,300 medications to coli strain IBDS1 and its isogenic mutant deprived of SOS
reveal the agents which could halt the mutations in S. pneu- mutagenesis mediated TLS were treated with multiple
Anti-evolution Drugs Letters in Drug Design & Discovery, 2021, Vol. 18, No. 0 3

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Fig. (1). Targeting Mfd for anti-evolution potential against drug resistance. Role of Mfd inhibitors in the inhibition of ATP conversion to
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ADP. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

concentrations of ciprofloxacin, N-acetylcysteine or both in to retract the neoplasms. While the immunotherapeutics such
combination. The result revealed that N-acetylcysteine di- as cancer vaccines and chimeric antigen receptor (CAR)-T
minished the intracellular ROS levels (∼40%), SOS activa- cell therapy are revolutionizing cancer management, they are
tion (∼75%), and bacterial filamentation produced by sub- still ultra-expensive and out of reach for many patients.
inhibitory concentrations of ciprofloxacin. Notably, the SOS- Therefore, promoting the existing drugs is vital for dealing
mediated mutagenesis was completely abolished by N- with anti-cancer drug resistance from a global perspective.
acetylcysteine without affecting the ciprofloxacin’s antibac- Few such recently discovered anti-evolution strategies are
terial activity [13]. Thus, edavarone and N-acetylcysteine discussed here.
can be used as ‘anti-evolvability drugs’ (Fig. 3).
7. TARGETING HSP90 AND HSF1
6. ROLE OF ANTI-EVOLUTION DRUGS IN
A cancer cell's ability to evolve and acquire drug re-
CURTAILING CANCER EVOLUTION AND DRUG
sistance is the fundamental cause of failure to treat many
RESISTANCE
cancers. The traditional ‘shock and awe’ approach of chemo-
Like bacteria evolve resistance to antibiotics, cancer cells therapy eventually fails because of the concept of ‘survival
could also emerge as multi-drug-resistant due to spontaneous of the nastiest’. Scientists have started to work on anti-
mutations. Consequently, most of the anti-cancer drugs fail evolution drugs to arrest cancer cells from developing
4 Letters in Drug Design & Discovery, 2021, Vol. 18, No. 0 Peraman et al.

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Fig. (2). Targeting proton motice force (PMF) for anti-evolution potential against drug resistance. The figure illustrates Triclosan as COM
blocker that inhibits the release of resistance material. (A higher resolution / colour version of this figure is available in the electronic copy of
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the article).
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Fig. (3). Targeting ROS for anti-evolution potential against drug resistance. Figure illustrates edavarone inhibit ROS activity targetting Sig-
ma-S (sS) mediated DNA repair. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
Anti-evolution Drugs Letters in Drug Design & Discovery, 2021, Vol. 18, No. 0 5

resistance to drugs. Over a period, researchers from The In- The Centre for Cancer Drug Discovery, London, has
stitute of Cancer Research (ICR), London, studied the effects studied the behaviour of cancer cells to different drugs using
of a 90 kDa heat shock protein (Hsp90). It is a chaperone artificial intelligence. Subsequently, a new class of apolipo-
protein involved in cell signalling, oncogenesis, and cancer protein B mRNA-editing enzyme catalytic polypeptide like
progression. Besides, it is also responsible for the self- (APOBEC) inhibitors was identified, which decreased the
protection of cancer cells under stress [14, 15]. Hsp90 inhibi- swiftness of treatment-resistant evolution in cancer cells.
tory potential was found to be effective in the preclinical
studies on colorectal cancer combined with 5-fluorouracil 8. TARGETING APOBEC
[16]. Hsp90 inhibitors also influence an essential stress con-
Next-generation sequencing (NGS) enabled geneticists to
troller in cancer cells called heat shock factor 1 (HSF1).
explore the human genome and acknowledge the intricacies
Thus, these findings paved the way for developing combina- associated with the evolution of cancer cells. APOBEC is a
tion treatments to stop cancer evolution and drug resistance. centroid of research for many virologists in the past decade
The Institute of Cancer Research (ICR) introduced a ‘multi- due to its importance in the evolution of HIV and cancer
drug herding’ technique in cancer treatment. This technique [17]. APOBEC is the family of ssDNA cytosine deaminase
involves the induction of cancer DNA to adapt to one treat- found in humans. The implications of APOBEC-catalysed
ment by developing weakness against others. It was just like DNA damage and mutagenesis in the evolution of 17 types
HIV medication where it does not cure but afford long life of cancer were uncovered through a series of studies with
expectancy (Fig. 4). NGS [18, 19]. It is a leading cause of development of clini-
cally resistant cancers through the activation of oncogenic

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Fig. (4). Targeting Hsp for anti-evolution potential against drug resistance. The figure illustrate the inhibitory effect on HsP90 which inhibit
the formation of protecting cancer cell through inhibition of heat shock protein 90. (A higher resolution / colour version of this figure is
available in the electronic copy of the article).
6 Letters in Drug Design & Discovery, 2021, Vol. 18, No. 0 Peraman et al.

drivers and diversification of tumour subclones [20]. The checkpoint (SAC) and chromosomal alignment. MPS1 kinase
normal function of APOBEC proteins is to create immune is a fundamental component of the SAC that directs the divid-
diversity to fight against new diseases as a part of innate ing cell from metaphase to anaphase by recruiting kinetochore
immunity. Though APOBEC enzymes are not derived from components required for microtubule assembly [23].
oncogenes, they were activated on the cancer genomes and BOS172722 mediated inhibition of MPS1 induces chromo-
influenced the development and progression of cancers. Tu- some missegregation of errors and decreases cancer cell via-
mour cells hijack the APOBEC abilities to create genetic bility. The anticancer properties of BOS172722 were tested on
diversity in their subclones and thereby evolve resistance. A triple-negative breast cancer (TNBC) cells which possess the
recent study by Matsumoto et al. 2019 revealed that phos- characteristics of basal-like breast cancer in addition to over-
phokinase A (PkA) could physically bind with APOBEC3B expression of human epidermal growth receptor 2 (HER2). A
cytidine deaminase (A3B) and phosphorylates it at Thr214 mechanistic synergy was observed when BOS172722 is com-
position [21]. They further confirmed that the phosphomi- bined with paclitaxel in targeting the dividing cells.
metic A3B mutants had lost their ability to edit foreign Treatment with paclitaxel alone arrests the mitosis by
DNA. Additionally, these mutants could generate an innate modifying the dynamics of microtubules and retardation of
immune response and exert tendentious protection from ret- SAC activity. However, TNBC cells evade the mitotic arrest
roviral infection. Thus, phosphorylation of A3B arbitrated by and excrete the paclitaxel, which resulted in the survival of
PkA would open a new field of opportunity to restrain the 40% of cells. With the addition of BOS172722, a dual nega-
evolution of cancer cells. tive force on mitotic arrest coupled with the inhibition of
MPS1 yielded absolute mortality of the cancer cells. The
9. TARGETING MPS1 combination is well-tolerated at lower doses in the mice.
Consequently, it had been escalated to phase I trials in com-
A drug molecule BOS172722 developed by the scientists

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bination with paclitaxel [24]. BOS172722 has a superlative
from the ICR, London, demonstrated promising attributes in

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potential among the modern approaches to the treatment of
curtailing the growth of the breast cancer cells in conjunction breast cancer. It is imperative to curtail cancer growth by

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with paclitaxel, a microtubule inhibitor [22]. It can inhibit a using multiple therapies to prevent the metastasis of drug-
serine/threonine-protein kinase monopolar spindle 1 (MPS1),

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resistant carcinomas (Fig. 5). Overall, the list of molecules
a dual-specificity protein kinase expressed in healthy tissues with anti-evolution potential is shown in Fig. (6), along with
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but abnormally overexpressed in various tumour cells. It is
se the targeting mechanism.
activated during mitosis and is essential in spindle assembly
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Fig. (5). Targeting MPS1 for anti-evolution potential against drug resistance. The figure illustrate the effect of inhibition of MPS1 with
chemical agents that results in inhibition of cell cycle targeting at metaphase, telophase and spindle assembly check point. (A higher resolu-
tion / colour version of this figure is available in the electronic copy of the article).
Anti-evolution Drugs Letters in Drug Design & Discovery, 2021, Vol. 18, No. 0 7

S N damental research on resistant microorganisms to recognise

H2N NH2
N
and examine how to handle such pathogens to address drug
resistance.
Thiourea (ROS inhibitor) 2,2'-bipyridine (ROS inhibitor)

LIST OF ABBREVIATIONS
O HO AMR = Anti-Microbial Resistance
O

N
N
HS HN
O Mtb = Mycobacterium tuberculosis
H3C
CH3
Mfd = Mutation frequency decline
Edaravone (ROS inhibitor)
N-Acetylcysteine (ROS inhibitor)
PMF = Proton-Motive Force
CSP = Competence Stimulating Peptide
H3C
N
H3C N COM = Competence
N N OH Cl
N O TPI2 = Topoisomerase II
N N
H
HN O Cl Cl TLS = Translesion Synthesis
CH3
CH3
H3C CH3 ROS = Reactive Oxygen Species
Triclosan (COM blocker)
BOS172722 (Mps1 inhibitor) SOS = Save Our Souls

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sS = sigma-S

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MBR = Mutagenic DNA Break Repair

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U ofs Cl dsDNA = double-stranded DNA

O
O CH3 NH2 NH2
NH
H3C N N N
Hsp90 = Heat shock protein 90
N
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H
F N se HSF1 = Heat Shock Factor 1
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Pimozide (COM blocker)

NGS = Next-generation sequencing
Proguanil (COM blocker)
APOBEC = Apolipoprotein B mRNA-editing
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Fig. (6). Reported chemical molecules with anti-evolution potential

enzyme catalytic polypeptide like
with appropriate mechanism.
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PkA = Phosphokinase A
A3B = APOBEC3B cytidine deaminase
A

CONCLUSION MPS1 = Monopolar Spindle 1

It is a common phenomenon in pathogens to acquire re- SAC = spindle assembly checkpoint
sistance to antibiotics. It is even possible for anti-evolution
drugs also. However, most of the anti-evolution drugs target TNBC = Triple Negative Breast Cancer
or

the fundamental needs of the organism, such as mutation and HER2 = Human Epidermal Growth Receptor 2
transfer of genes. Therefore, even if the organism prefers to
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shut down its basic needs in a quest to develop resistance to SARS-CoV-2 = Severe Acute Respiratory Syndrome
anti-evolution drugs, it is still susceptible to antibiotics. Coronavirus 2
Hence, this approach acts as a double-edged sword to com-
bat the AMR. With the recent advancement in molecular ETHICS APPROVAL AND CONSENT TO
research, scientists can now successfully target the evolvabil- PARTICIPATE
ity factors such as Mfd, PMF, competence, and ROS. Few
studies have even identified several FDA-approved drugs Not applicable.
that can inhibit these evolution mechanisms. The next step is
to perform clinical studies to prove their safety and efficacy. HUMAN AND ANIMAL RIGHTS
The practice of medicine varies across the countries No Animals/Humans were used for studies that are the
based on the disease burden, immunity of the population, basis of this research.
and economy. Due to these variations, the evolution of the
pathogen and the pattern of resistance also differ. Consider- CONSENT FOR PUBLICATION
ing the current burden of AMR, it is imperative to act
promptly and take the necessary steps to impede the spread Not applicable.
of resistant species. Further, the recent SARS-CoV-2 pan-
demic highlighted the need for sophisticated healthcare sys- AVAILABILITY OF DATA AND MATERIALS
tems and drug discovery practices to handle the newly evolv-
ing pathogens. Therefore, it is necessary to take up the fun- Not applicable.
8 Letters in Drug Design & Discovery, 2021, Vol. 18, No. 0 Peraman et al.

FUNDING ulation differentiated by reactive-oxygen-induced general stress re-

sponse. Mol. Cell, 2019, 74(4), 785-800.e7.
The authors are thankful to the Department of Science http://dx.doi.org/10.1016/j.molcel.2019.02.037 PMID: 30948267
and Technology (DST), New Delhi, for funding the devel- [12] Liu, Y.; Liu, X.; Qu, Y.; Wang, X.; Li, L.; Zhao, X. Inhibitors of
opment of a facility on antimicrobial research vides applica- reactive oxygen species accumulation delay and/or reduce the le-
thality of several antistaphylococcal agents. Antimicrob. Agents
tion no. SR/FST/College-004/2017.
Chemother., 2012, 56(11), 6048-6050.
http://dx.doi.org/10.1128/AAC.00754-12 PMID: 22948880
CONFLICT OF INTEREST [13] Rodríguez-Rosado, A.I.; Valencia, E.Y.; Rodríguez-Rojas, A.;
Costas, C.; Galhardo, R.S.; Rodríguez-Beltrán, J.; Blázquez, J. N-
The authors declare no conflict of interest, financial or acetylcysteine blocks SOS induction and mutagenesis produced by
otherwise. fluoroquinolones in escherichia coli. J. Antimicrob. Chemother.,
2019, 74(8), 2188-2196.
http://dx.doi.org/10.1093/jac/dkz210 PMID: 31102529
ACKNOWLEDGEMENT [14] Butler, L.M.; Ferraldeschi, R.; Armstrong, H.K.; Centenera, M.M.;
Workman, P. Maximizing the therapeutic potential of hsp90 inhibi-
Declared none. tors. Mol. Cancer Res., 2015, 13(11), 1445-1451.
http://dx.doi.org/10.1158/1541-7786.MCR-15-0234 PMID:
26219697
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