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18.4 Medicinal Chemistry Strategies for the Design of Antibacterials Combating Multidrug-Resistant Bacterial Infections 413
O
NH
NH
2
O
NH
H
2
N
Pentamidine
HO
O
N
H
O O
OH
O
O
O
OH
O
O NH
2
Novobiocin
O
H
N
O
N
H
O
H
N
O
N
H
O NH
O
N
H
O
NH
O
HN
OHN
O
H
N
O
NH
HO
NH
2
NH
2
H
2
N
NH
2
OH
NH
2
Colistin
N
N
N
OH
O
O
O
O
O
OH
OH
OHN
HO
HO
O
Rifampicin
O
H
N
O
N
H
OH
O
H
N
S
S
N
H
O
HN
O
NH
O
NH
O
N
H
O
HN
O
NHO
O
NH
2
NH
HN
NH
2
HN NH
NH
2
HO
NH
2
OHN
O
NH
2
O
NH
NH
NH
H
2
N
O NH
S
O
OH
N
H
O
N
O
NH
O
NO
NH
2
HN
O
H
2
N
NH
O
HO
N
H
O
H
2
N
Thanatin
Similarly, the combination therapy of antibacterial drugs along with efflux pump inhibitors can
make the antimicrobial agent available for a longer period at the target site to exert its potential
action. Loperamide along with minocycline, econazole along with colistin, tobramycin-lysine
hybrid along with novobiocin, etc., work efficiently in this way. In recent years, the combination of
biofilm damages along with antimicrobial agents is also used in combined therapy.
18 Rational Design of Antibacterial Agents for Multidrug-Resistant Infections414
Cl
N
N
O
OH
Loperamide
N
OO OH
OH
O
NH
2
OH
N
OH
Minocycline
Econazole
O
H
N
O
N
H
O
H
N
O
N
H
O NH
O
N
H
O
NH
O
HN
OHN
O
H
N
O
NH
HO
NH
2
NH
2
H
2
N
NH
2
OH
NH
2
Colistin
Cl
Cl
O
Cl
N
N
NH
2
O
O
OH
OH
NH
2
OHOH
O
O
H
2
N
HO
NH
2
H
2
N
HO
O
N
H
O O
OH
O
O
O
OH
O
O NH
2
Tobramycin Novobiocin
18.4.7 Drug Repurposing
It includes examining current medications for any novel antibacterial qualities. Finding new
applications for medications that were first created for different purposes is known as drug
repurposing. This strategy can hasten the process of developing new drugs. The phosphoinositide
3-kinase inhibitors are repurposed to use as adjuvants in the treatment of bacterial infections;
repurposing of novel β-lactams and polymyxins along with adjuvants (nonantibiotics) like
antibiotic inactivating enzyme inhibitors, membrane permeabilizes, efflux pump inhibitors, and
biofilm damages are some of the reported examples of drug-repurposing approaches in MDR
antibacterial drug development [44].
18.4.8 Resistant Mechanism Blocking
Create medications that block particular resistance pathways, like efflux pumps, decreased perme-
ability, or the enzymes that render a medication inactive. Combining these inhibitors with existing
antibiotics can enhance their effectiveness. Cefiderocol is a siderophore cephalosporin that
improves entry into bacterial cells by taking advantage of the iron transport system in bacteria,
hence circumventing some resistance mechanisms [45].
18.4 Medicinal Chemistry Strategies for the Design of Antibacterials Combating Multidrug-Resistant Bacterial Infections 415
O
HO
O
N
S
N
H
2
N
O
H
N
N
O
S
N
+
HN
O
HO
HO
Cl
O
O
–
Cefiderocol
18.4.9 Improving Drug Delivery by Nanotechnology
Combining antibiotics with nanomaterial compounds also known as nano-antibiotics is another
innovative way to boost the efficacy of antibiotics. For instance, vancomycin nanoformulation has
increased antibacterial action against multidrug-resistant pathogens such as vancomycin-resistant
Enterococcus and methicillin-resistant Staphylococcus aureus when coupled with silver nanoparticles.
Nanotechnology was employed to reduce adverse effects on host cells. Nanoparticles and nanocarriers
can maximize drug stability,bioavailability, and targeted delivery to bacterial cells. Recently, ampicillin
silver (AgNPs) and gold nanoparticles (AuNPs) were proven as broad-spectrum antibacterial agents to
overcome the resistance against multidrug-resistant strains of bacterial species functionalized with
vancomycinand were developed to combat vancomycin-resistant enterococci. The antibacterial activity
of alginate nanoparticles comprising colistin showed more potent activity against colistin-resistant
bacterial strains. Similarly, linezolid bound to silver/gold bimetallic nanoparticles (Au@Ag@Lz)
showed significant efficacy even against methicillin-resistant Staphylococcus aureus [46].
N
S
O
N
H
O
H
2
N
O
HO
Ag
Ampicillin silver nanoparticles
N
S
O
N
H
O
H
2
N
O
HO
Au
Ampicillin gold nanoparticles
O
O
O O
O
Cl
O
N
H
O H
N
O
N
H
HO
OH
HN
O
Cl
O
OH
H
N
O
O
OH
HO
O
NH
2
H
N
O
NH
HO
HO
HO
OH
H
2
N
OH
+COOH
SAg
Vancomycin-Ag Nanoparticle
18 Rational Design of Antibacterial Agents for Multidrug-Resistant Infections416
18.4.10 Phage Intervention
Examine the potential applications of bacteriophages and viruses that infect bacteria as a medical
strategy. Phage therapy offers a precise and focused method of eliminating bacteria, and phages
can change over time to combat resistance in bacteria. The host range of lytic phages is determined
by the fact that the majority of them are only infectious to bacteria that also carry their
corresponding receptor. Phages differ in their host specificity; some are strain specific, while
others can infect various bacterial strains and even species. Bacteria have developed a multitude
of defense mechanisms against lytic phage infection, while phages have amassed an equally
remarkable array of defense mechanisms against this resistance. This can involve the deletion or
mutation of receptors in bacteria as well as the integration of phage DNA into the CRISPR/Cas
system, which is a clustered regularly interspaced palindromic repeats system. For phages, this
can involve the detection of anti-CRISPR genes and new or altered receptors. For the first time,
bacterial phases were used to treat pediatric dysentery in 1919. Phase therapy was continued in
the 20th century for treating cholera, dysentery, and bubonic plague through the production of
bacteriophage preparations on a commercial scale. Recent works revealed that therapy with
phase preparations significantly improved P. aeruginosa gut-derived sepsis. In animal models,
phage cocktails have also been utilized to treat resistant P. aeruginosa infections that affect the
skin, lungs, and digestive system [47].
18.4.11 Host Targeting
Bacteria such as Mycobacterium tuberculosis and Coxiella burnetii can delay or avoid the fusion of their
vacuoles with lysosomes and develop a replicate niche that helps to escape from phagosomes thereby
entering into the cytosol. Designing potential drugs that specifically target host cell elements like the
resolution of signaling pathways, enhancing the autophagy activity, stabilizing and improvingthe innate
immune pathways, adapting the neutralizing mechanism for reactive species, and reducing the host
proinflammatory response are the ways through which the bacterial life cycle can be disturbed, and the
likelihood of bacterial resistance development is reduced by altering host factors. For instance, when
monophosphoryl lipid A, a chemically altered derivative of the lipid A moiety of lipopolysaccharide, was
inhaled, the amount of Moraxella catarrhalis and Haemophilus influenzae bacteria that were collected
from the nasopharynx was significantly lower . The Escherichia coli infection in the bladder was greatly
reduced (10-fold) by administration of an HIF-1α-stabilizing agent (AKB-4924) [48].
18.4.12 CRISPR-Cas Technique
Make use of CRISPR-Cas technology to target and remove specific DNA from bacteria. This
method can target particular bacterial strains that are prone to ABR precisely because of their high
selectivity. For instance, the viability of E. coli was drastically reduced by targeting the virulence
factor gene eae, which is essential for the pathology and colonization of these bacteria by CRISPR-
Cas technique. Similarly, this technique was employed to potentiate the bactericidal activity of
carbapenem against E. coli by targeting resistance genes such as blaOXA-48 and bla IMP-1 and
colistin against E. coli by targeting resistance genes like mcr-1&2 [49].
18.4.13 Peptides as Antibacterials
The application of antimicrobial peptides (AMPs) can damage bacterial membranes or obstruct vital
bacterial processes. These peptides might be less likely to develop resistance and exhibit
18.4 Medicinal Chemistry Strategies for the Design of Antibacterials Combating Multidrug-Resistant Bacterial Infections 417
broad-spectrum activity. The first AMP discovered and isolated in 1939 from soil Bacillus brevis is
gramicidin; it exhibits its antimicrobial action by affecting the strength or disruption of bacterial cell
walls through different types of interactions. For instance, the biofilms formed in K. pneumonia-
resistant drugs like imipenem, meropenem, and cefepime were efficiently encountered by the
protease-resistant peptide. Similarly, the peptide and its derivatives isolated from the frog skin secre-
tions showed better therapeutic activity against biofilms of Enterococcus faecalis and methicillin-
resistant S. aureus [50].
18.4.14 Immunizations and Immunotherapy
Make investments in the creation of vaccines to combat bacterial strains resistant to antibiotics. As
an addition to traditional antimicrobial treatments, immunotherapies that strengthen the host
immune response against bacterial infections may be investigated. For instance, Raxibacumab
toxin a monoclonal antibody was proven to be effective in the treatment of anthrax caused by
B. anthraci, the monoclonal antibody Bexlotoxumab was developed for treating recurrent
Clostridium difficile infections [51].
18.4.15 Natural Product Derivatives
Since many of the antibiotics currently in use are derived from natural products, exploring and
modifying compounds derived from natural sources might be hopeful in this drug discovery. So
many natural compounds were reported for antibacterial activity against different bacteria,
Piperine is potent against Lactobacillus and Micrococcus, and anthemic acid is potent against
M. tuberculosis, Staphylococcus aureus, etc. [52].
18.4.16 Fragment-Based Drug Discovery (FBDD)
This method entails determining the interactions that low-molecular-weight molecules
(100–300 Da) have with their potential targets, frequently at low affinity (KD ~0.1–1 mM).
Beginning with tiny chemical fragments and working your way up to more complex compounds
can bind effectively to bacterial targets. The fragments with low molecular weight to high molec-
ular weight biologically active compounds were screened for potential antibacterial activity
against bacterial targets like Biotin Carboxylase, DNA Gyrase, Cell Division Protein FtsZ, and
β-lactamase [53, 54].
18.4.17 Metabolomics and Genetics
Integrating information from bacterial genetics with metabolomics uncovers new targets and
pathways that can be exploited for antibiotic development.
18.4.18 Cheminformatics
The study of chemical data analysis and the prediction of novel compounds’ antibacterial activity
through the use of algorithms and data analysis tools such as SwissADMET, Drugmint,
SwissBioisostere, pkCSM, DataWarrior, Galaxy, BioTransformer, and Knime for determining drug-
likeness, and ADMET properties. [55, 56].
18 Rational Design of Antibacterial Agents for Multidrug-Resistant Infections418
18.5 Summary and Conclusion
In summary, bacterial infections, with their various origins, symptoms, and developing treatment
approaches, continue to pose a serious threat to global health. Current outbreaks highlight the
enduring danger presented by bacterial infections and the pressing need to create efficient defenses
against them. Treatment attempts are made more difficult by the emergence of antimicrobial resist-
ance, which calls for a deeper comprehension of the fundamental mechanisms causing resistance.
Antimicrobial resistance has been shown to occur through multiple methods, such as genetic
changes, HGT, and biofilm formation. These mechanisms pose significant challenges to conven-
tional antibiotic therapy. Additionally, the emergence of antibiotic resistance makes clinical man-
agement of bacterial infections even more difficult, restricting available treatments and raising
death rates.
A multidisciplinary strategy that includes creative antibacterial drug creation techniques and
coordinated attempts to tackle resistance mechanisms is needed to address these issues. Novel
therapeutic targets are necessary, and improvements in combination therapy and drug delivery
methods present intriguing paths to overcome resistance.
However, creating antibacterial medications that work against resistant types of bacteria is still
a difficult endeavor with many unknowns in science. The intricate relationship that exists between
host–pathogen interactions, environmental variables, and bacterial physiology highlights the
importance of interdisciplinary collaboration and integrated research efforts.
In light of these factors, a number of approaches, such as target validation, structure-based drug
design, and repurposing of already-existing molecules, have enormous potential in the search for
next-generation antibacterial medicines. Adopting a comprehensive strategy that combines prot-
eomic, genomic, and computational techniques can spur the creation of novel treatments that can
evade resistance mechanisms and protect public health.
In conclusion, the fight against bacterial infections and antibiotic resistance necessitates persis-
tent attention to detail, creative thinking on the part of scientists and cooperative efforts from a wide
range of stakeholders. Through the utilization of state-of-the-art technologies and the promotion of
an innovative culture, it is possible to reduce the effects of pathogen resistance and maintain the
effectiveness of antibacterial treatments for future generations. This chapter explained the bacterial
infections: causes, symptoms, symptoms, and recent outbreaks of bacterial infections, elaborated
treatment strategies, development of resistance against the antimicrobial agents, i.e., antimicrobial
resistance, and mechanisms involved in developing antimicrobial resistance or MDR. This chapter
also briefed about the essentiality and challenges in antibacterial drug design against resistant bac-
teria shown through different mechanisms. Further , it described the various strategies that can be
effective in antibacterial drug design against multidrug-resistant strains. The information provided
in this chapter might be made knowledgeable and enlighten them with different thought processes.
Hence, this information might be helpful in novel antibacterial drug design and development
against vulnerable and endangered MDR bacterial infections in the future.
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