Naina Kalra 35802

Antimicrobial Chemotherapy and Mechanisms of

Antibiotic Resistance

Introduction
The evidence of chemotherapy that has been successful in the past is when Indians used cinchona
tree’s bark for the treatment of malaria in 17th century. However in 20th century the modern world
started the extensive use of chemotherapy with the rapid emergence of microbial infections.
Chemotherapy refers to the use of chemical agents against microbes. Ideal chemotherapeutic agents
have selective toxicity .i.e. the drug only targets the pathogen but not the host which is achieved by
selecting the target of antimicrobial drugs to be only present in microbes but not in host. The major
mechanisms of action can be divided into 4 categories (Geo F. Brooks et al., 2012; Al-mohanna,
2017).

1) Inhibition of Cell Wall Synthesis

The important target site for antibiotic is peptidoglycans layer. B-lactams are the most important
antibiotics that inhibit the formation of
layer. Beta lactams inhibit transpeptidases
(penicillin binding proteins) thus
inhibiting the cross-binding between the
peptide side chains.
Glycopeptide antibiotics such as
vancomycin binds to the D-alanyl-D-
alanine of peptide side chain and prevent
cross-binding.
Also, NAM and NAG secretion from cytoplasm is blocked by bacitracin (Gootz et al., 1996;
Kapoor G., Saigal1 S., 2017).

2) Inhibition of Synthesis of Protein

 Elongation of protein is inhibited by macrolides that bind to 50S subunit of ribosomes.
Peptidyltransferase (peptide forming enzymes) is inhibited in this process.

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 The 30S subunit of ribosomes is distorted by aminoglycosides in such a way that tRNA
containing anticodons inappropriately align with the codons presents on mRNA and hence,
interfering with the polypeptide formation (Gootz et al., 1996).

3) Inhibition of Nucleic Acid Synthesis

Synthesis of nucleic acid can be impaired by several mechanisms
 DNA-Directed RNA Polymerase Inhibition
DNA directed RNA polymerase is inhibited by Rifamycins which binds to the subunit of
RNA polymerase that recognizes the promoter region on the DNA and starts
transcription. As a
result, initiation process
is interfered and
transcrition does not
take place (Gootz et al.,
1996).
 Inhibition of DNA Replication
DNA gyrase is responsible for DNA supercoiling. Antibiotics such as quinolones
interfere with DNA gyrase which cleaves the DNA and then reseal it. Quinolone binds
with DNA cleavage complex and stabilizes it thus inhibiting DNA replication and hence,
occurrence of cell death. Quinolone also interfere with topoisomerase IV and does not
allow the replicated daughter chromosomes to separate (Gootz et al., 1996).

4) Inhibition of Cell Membrane Synthesis

Many cationic, anionic and neutral antimicrobial agents cause disintegration of cell membrane of
microbes.
Many antimicrobial drugs cannot cross the barriers of cell membrane. Therefore the aim of some
antimicrobial agents (such as polymixin B) is to increase the permeability of cell membrane and
make the passage of disrupting anions, cations and neutral compound into the cell easier (Gootz
et al., 1996).
Several function of polymixin B have been observed which are as follows
 Cytoplasm membrane depolarization
 Disturbance of surface change

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 Disturbance in lipid composition

 Disturbance in structure of cell membrane

Mechanisms of Antibiotic Resistance

The microbial resistance has become a major problem in the clinical world as microbes evolve time
to time and the interventions fail.
There are some basic mechanisms that are present in microbes for resistance which are as follows;

 Alteration in the Receptors Leads to Target Site Modification

Antimicrobial agents are specific for a specific target site therefore minute change of the target
site affects the binding of target molecules and antimicrobial agents.
Altered protein binding proteins resistance in several microbes such as S.pneumoniae,
N.gonorrhoeae and Staphylococcus aureus is due to the synthesis of altered PBPs. This
resistance is developed against B.lactam antibiotics and the altered PBPs have lowered affinity
for these antibiotics. Alteration in PBP2b has been observed in case of pencillin whereas third
generation cephalosporins leads to the PBP1a and 2x alteration of bacteria. These alterations are
due to the recombination of PBP genes and acquired by transformation between two microbes
(Liwa C. et al., 2015).

i. Modification in the Peptides Side Chain of Peptidoglycan

Layer
Vancomycin can only bind D-alanyl-D-alanine of the peptide side chain of peptidoglycan
layer and consequently does not allow the side chain to form cross bridge. In certain
bacterial species some transposable genes encode different enzymes that synthesize D-
alanyl-D-lactate instead of D-alanyl-D-alanine which has the decrease affinity for
vancomycin and hence bacteria develop resistance.

ii. Modification of Enzymes Involve in DNA Synthesis

Quinolone act as topoisomerases and impair DNA synthesis by forming a drug enzyme
DNA complex which leads to the breaks in the double stranded DNA
Resistance is acquired by the mutation in gryA and parC genes encoding DNA gyrase and
topoisomerase IV respectively. As a result modified enzymes are synthesized that have

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the low affinity for the antimicrobial agents. This resistance can either be acquired by
bacteria by point mutation in gryA and parC or it might be ribosomal methylation.

iii. Ribosomal Methylation

Other mechanism may include the modification in the 23S RNA of larger subunit of
ribosomes .i.e. two adenine nucleotide methylation. This is also plasmid mediated as in
staphylococci, plasmid consistently pass between species (Liwa C. & et al., 2015).

 Inactivation of Antimicrobial Agents

The three main enzymes involve in drug inactivation are
i. B-lactamase ─ All B-lactams that contain amide and
ester bonds are hydrolyzed by B-lactamases that
breaks their B-lactam ring and form an acid that
supports the further hydrolysis of B-lactams.
ii. Aminoglycoside-modifying and chloramphenicol-
modifying enzymes ─ Transferases and
chloramphenicol enzymes inactivate aminoglycosides
and chloramphenicol by group transfer (Liwa C. & et al., 2015; Kapoor G., Saigall S., 2017).

Decreased Permeability of Membrane

i. The composition of gram negative cell wall (phospolipid inner layer and lipid A in outer
layer) reduces transfer of drugs through the cell wall (through porin protein) and hence drug
uptake decreases. Therefore larger molecules such as aminoglycosides cannot transfer
through porins.
ii. Also a membrane protein encoded by efflux resistance gene actively transports the antibiotics
out of the cell .e.g. tetracycline (Liwa C. & et al., 2015; Kapoor G., Saigall S., 2017).

Conclusion
Various chemotherapeutic agents have been synthesized commercially for the prevention and cure of
certain microbial infection. Different classes of chemotherapeutic agents interfere with synthesis and
functioning of different components of microbes. However, continuous efforts and research is
required as microbes evolve time to time and show effective resistance against antibiotics.

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References
Al-mohanna, M. T. Antibiotics and chemotherapeutic agents; 2016.
Garima Kapoor, Saurabh Saigal1, A. E. Action and resistance mechanisms of antibiotics: A guide for clinicians.
Journal of Anaesthesiology Clinical Pharmacology, 2017;33(3), 11.
Geo F. Brooks, Karen C. Carroll, Janet S. Butel, Stephen A. Morse, Timothy A. Mietzner. Jawetz, Melnick, &
Adelberg's Medical Microbiology 26th edition. McGraw-Hill; 2012.

Neu HC, Gootz TD. Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas
Medical Branch at Galveston; 1996.

Liwa, A. C., & Jaka, H. Antimicrobial resistance: Mechanisms of action of antimicrobial agents. The Battle
Against Microbial Pathogens: Basic Science, Technological Advances and Educational Programs, 2015;
876–885.

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