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Bacterial cells are surrounded by a peptidoglycan cell wall, which consists of long polymers of
sugar. The antibiotics which inhibit cell wall synthesis are following:
Beta-lactam antibiotics
The primary targets of the β-lactam agents are the penicillin binding proteins (PBPs).
Researchers have hypothesized that the β-lactam ring mimics the D-alanyl D-alanine portion of
peptide chain that is normally bound by PBP. The interaction of PBP with β-lactam leads to the
unavailable of PBPs for the synthesis of new peptidoglycan. The disruption of layer of
peptidoglycan triggers the lysis of bacterium (Figure 3) (Džidic et al., 2008).
Figure 2: Mechanism of action of β-lactam antibiotics.
Glycopeptides
Glycopeptides act by binding to D-alanyl D-alanine portion of peptide side chain which is the
precursor of peptidoglycan subunit. The large drug molecule vancomycin inhibits the binding of
this D-alanyl subunit with the PBPs, and ultimately preventing cell wall synthesis (Džidic et al.,
2008).
In bacteria, first a RNA molecule referred to as messenger RNA (m-RNA) is synthesized using
bacterial DNA information in a process known as transcription. Then proteins are synthesized by
using this m-RNA with the help of ribosomes, in the process of translation. Protein biosynthesis
is catalyzed by ribosomes and cytoplasmic factors. The 70S ribosome of bacteria is composed of
two ribonucleoprotein subunits: the 30S and 50S subunits. Antibiotics inhibit protein
biosynthesis by targeting bacterial ribosome 30S or 50S subunit (Figure 3) (Johnston et al.,
2002).
Aminoglycosides
The aminoglycosides (AG's) are positively-charged molecules which attach to the negatively
charged OM leading to formation of large pores, and thus aiding in antibiotic penetration inside
the bacterium. These AG’s can be used with those antibiotics, which inhibit cell wall synthesis
(such as β-lactam and glycopeptides) as it allows greater penetration of AG within the cell and at
low dosages. AG's interact with the 16S r-RNA of the 30S subunit near the A site through
hydrogen bonds and finally causing misreading and premature termination of m-RNA translation
(Yoneyama and Katsumata. 2006).
Tetracyclines
Chloramphenicol
It interacts with the conserved sequences of the peptidyl transferase cavity in the 23S r-RNA at
the 50S subunit, thus inhibiting the protein synthesis by preventing binding of t-RNA to the A
site of the ribosome (Yoneyama and Katsumata. 2006).
Macrolides
Macrolides affect the early stage of protein synthesis, translocation, by targeting the conserved
sequences of the peptidyl transferase center of the 23S r-RNA of the 50S ribosomal subunits,
leading to a premature detachment of incomplete peptide chains. Macrolides, streptogramins B,
and lincosamides show a similar mechanism of action.
Oxazolidinones
Linezolid is a completely synthetic and recently approved member of novel class of antibiotic.
Oxazolidinones interfere with protein synthesis at several stages: (i) inhibition of protein
synthesis by binding to 23Sr RNA and (ii) suppress inhibition of 70S and interact with peptidyl-
t-RNA (Bozdogan and Appelbaum. 2004).
Quinilones
The fluoroquinolones (FQ) inhibit the bacterial enzyme DNA gyrase, which nicks the dsDNA,
followed by negative supercoils formation and then reseals the nicked ends. During replication or
transcription, it is necessary to prevent excessive positive supercoiling of the strands when they
separate. The DNA gyrase consists of two A subunits and two B subunits. A subunit carries out
the nicking of DNA, B subunit introduces negative supercoils, and then A subunit reseal the
strands. The FQ's binds with high affinity to A subunit and interfere with its function.
topoisomerase IV which nicks and separate's daughter DNA strand after DNA replication, is the
major target of action in Gram-positive bacteria (Wise. 1999; Kapoor et al., 2017)
Distinct steps in folic acid metabolism are inhibited by each of these drugs. A combination of
sulpha drugs and trimethoprim if used at distinct steps on the same biosynthetic pathway shows a
reduced mutation rate for resistance. Sulfonamides in a competitive manner inhibit
dihydropteroate synthase with higher affinity for the enzyme than the natural substrate, p-amino
benzoic acid. Agents such as trimethoprim act at a last stage of folic acid synthesis and inhibit
the enzyme dihydrofolate reductase (Kapoor et al., 2017).
References:
Johnston NJ, Mukhtar TA, Wright GD. Streptogramin antibiotics: Mode of action and
resistance. Curr Drug Targets. 2002;3:335–44.
Yoneyama H, Katsumata R. Antibiotic resistance in bacteria and its future for novel antibiotic
development. Biosci Biotechnol Biochem. 2006;70:1060–75.
Kapoor, G., Saigal, S., & Elongavan, A. (2017). Action and resistance mechanisms of
antibiotics: A guide for clinicians. Journal of anaesthesiology, clinical pharmacology, 33(3),
300.