Genetic Mechanism of Drug Resistance

Drug Resistance

Ability of microbes to grow in presence of chemical (drug) that would normally kill or limit its growth.
In turn, this reflects reduction in drug’s effectiveness in curing a disease or condition.

Types of drug resistance

1. Primary / natural /non-genetic origin of resistance

2. Acquired / genetic origin of drug resistance

Here, bacteria acquire/develops antibiotic resistance
Either via modification of existing genetic material (mutation)
Or by new genetic material acquisition from another source (plasmid/gene transfer).

i. Inactivation of the antimicrobial drug

Resistance to penicillin and cephalosporin antibiotics

Production of an enzyme beta-lactamase, inactivates the antimicrobial agent
The most common mechanism of resistance is production of neutralizing enzymes by bacteria
Genes encoding betalactamases may be present on chromosome or plasmid.
These genes may be constitutively expressed or induced by a beta-lactam antibiotic.
Such form of resistance is seen in S.aureus, H.influenzae, E.coli, K.pneumoniae etc.

Resistance to Aminoglycoside

Aminoglycoside modifying enzymes destroy the drug by adenylylating, phosphorylating, or acetylating them.
The genes encoding for aminoglycoside modifying enzymes are usually found on plasmids and transposons.
Seen in members of Enterobacteriaceae, Acinetobactersps, Pseudomonas aeruginosa, S.aureus, Campylobacterjejuni etc.

ii. Alteration of the antimicrobial target

As a result of mutation, the targets of the antimicrobial agents get lost or altered.
Sometimes, the existing target may be replaced by an entirely novel protein.
Resistances to penicillins/cephalosporins in MRSA, S. pneumoniae or enterococci are often to due to production of altered/novel penicillin binding proteins.
Methylation of 23S ribosomal RNA renders the receptor on 50S subunit altered, thereby preventing the binding of erythromycin.
Mutations in the 30S subunit of the ribosome interfere with ribosomal binding of streptomycin.
Methylation of a single adenine in the bacterial 50s ribosome can lead to resistance against macrolides, lincosamides, and streptogramin B in S. aureus and S. pneumoniae.

iii. Adaptation of alternative metabolic pathway

Some sulfonamide-resistant bacteria do not require extracellular PABA but, like mammalian cells, can utilize preformed folic acid.
A mutational loss in bacteria make them dependent on an external supply of thymine, which contributes to trimethoprim resistance.
A mutational change in H. influenzae results in overproduction of dihydrofolate reductases, leading to trimethoprim resistance.

iv. Active efflux pumping out of the drug

Mutations in certain bacteria permit the over-expression of the efflux-pump protein.
Sometimes, an amino acid substitution in the efflux-pump protein makes it more efficient at export of the drug.
In either case, the intracellular antibiotic concentration is decreased and the bacterium becomes less susceptible to that antibiotic.
Seen to chloramphenicol (P.aeruginosa, K. pneumoniae, E. coli, S. typhimurium, V. cholerae), macrolides(erythromycin) (Streptococcus pneumoniae, Enterococcus sps, Bacteroides sps, Pseudomonas sps and Enterobacteriaceae members), tetracyclines (S. aureus, E. coli, A. baumannii, S. typhimurium), aminoglycosides (E. coli, P.aeruginosa, A. baumannii) and beta-lactams (H. influenzae, P.aeruginosa, A. baumannii).

v. Decreased permeability of the drug

Some strains of P. aeruginosa and other gram-negative bacilli exhibit aminoglycoside resistance due to a transport defect or membrane impermeabilization.
Resistance to cefoxitin in E. coli and K. pneumoniae is due to mutations leading to narrowed outer membrane proteins.

The most common mechanism of resistance is production of neutralizing enzymes by bacteria
Penicillinase production is transmitted by transduction is plasmid mediated
Methicillin resistance is due to change in PBP.
Complete elimination of target is the mechanism by which enterococci develop resistance to vancomycin
Alteration of target lesions leads to development of resistance to antibiotics in Streptococcus pneumoniae
Drug resistance in Tuberculosis is due to mutation and Rpo B Gene responsible for resistance to rifampicin
Mechanism of resistance to erythromycin

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