Antimicrobial Drug Resistance for NEET/AIIMS/USMLE/FMGE/PLAB Resistance to antimicrobial drugs can be either intrinsic or acquired.
1. Intrinsic Mechanisms
Intrinsic mechanism are natural ability of the bacteria to avoid a class of drugs due to specific functional or structural abilities as described below. These microbes were never susceptible to these antibiotics.
a. Poor Affinity of Antibiotics to Bacterial Targets
• Some bacterial targets have structures which antibiotics can do bind to or some even lack the target altogether.
• Burkholderia cepacia has a lipopolysaccharide on its cell membrane to which cationic drugs like aminoglycosides and polymyxins have no affinity.
• Gram positive organisms have a penicillin binding protein, to which aztreonam cannot bind and hence is active only against gram negatives.
• Similarly, enterococci have penicillin binding proteins, to which cephalosporins cannot bind.
• Mycoplasma does not have a cell wall and hence antibiotics inhibiting cell wall synthesis like beta lactams are not effective.
Poor Entry of Antibiotics Through Cell Wall
• Vancomycin has a huge size and hence it cannot enter through the small porins present on the cell wall of gram negatives.
• Aminoglycosides require oxygen for entry into bacteria, as oxygen generates a trans- membrane potential that attracts aminoglycosides through the cell wall. Hence aminoglycosides are not effective against anaerobes.
b. Drug Efflux of Antibiotics
• Efflux pumps which are chromosomally coded in Burkholderia Cepacia can pump out antibiotics like tetracyclines, chloramphenicol and ciprofloxacin.
c. Production of Drug Inactivating Enzymes
These enzymes are intrinsically present in the bacteria and not formed after exposure.
• Klebsiella produces beta lactamase that destroys ampicillin and S. maltophilia produces beta lactamase that destroys imipenem.
2. Acquired Mechanisms
Genetic Basis of Resistance
Acquired resistance by genes can be of two types based upon the mechanism of genetic change i.e. chromosome mediated and horizontal gene transfer.
a. Chromosome Mediated
Chromosome mediated resistance can be because of spontaneous mutation, hyper- mutation and adaptive mutation.
• Spontaneous mutation is a result of faulty DNA replication or repair of DNA damage seen during bacteria replication. This can bring about changes in the bacteria as described below:
■ Change of a target for the antibiotics that gene codes: Rpob gene mutation changes structure of RNA polymerase targeted by rifampicin.
■ Decreased or absence of gene for porin production in gram negatives: Decreased activity or absence of oprD gene in pseudomonas decreases porins and entry of antibiotics.
■ Activation of efflux pumps: E. coli mar gene mutation increases AcrAB pumps which cause efflux of beta lactams, fluoroquinolones and tetracyclines.
■ Upregulation of beta lactamase production due to mutation: Resistance to cephalosporins in gram negative organisms.
• Hypermutation is defined as an elevated mutation rate in bacteria that changes genes causing drug resistance e.g. multi drug resistance TB of Beijing genotype.
• Adaptive mutation unlike spontaneous mutation is seen in non-replicating bacteria. For e.g. exposure of quinolones causes mutation in E. coli.
Horizontal Gene Transfer
A gene containing drug resistance can be transferred either between bacteria or within a bacterium between chromosomes and plasmid.
• Transfer of resistance between bacteria i.e. from one bacterium to another can happen by three mechanisms conjugation, transduction and transformation.
■ Bacterial Conjugation: In conjugation there is a cell to cell transfer of genes present in plasmid through a sex pilus. This is the most common mechanism of drug resistance transfer.
■ Bacterial Transduction: In transduction, the gene containing resistance is transferred by a bacteriophage from one bacterium to another.
■ Bacterial Transformation: In transformation a naked DNA part containing resistance genes, released due to lysis of a bacteria is taken up and integrated to its DNA by another bacterium.
• Transfer of resistance within a bacterium between its chromosomes and plasmids with the help of transposons and integrons.
■ Integrons are elements present in bacterial DNA or plasmid, which with the help of integrase can integrate gene cassettes containing drug resistance into DNA or plasmid.
■ Transposons are part of chromosome in DNA or plasmid which can contain integrons. These transposons can breakdown from DNA or plasmid and get themselves incorporated into another plasmid. Hence, they will carry with them the integrons and transfer resistance from a chromosome of DNA to plasmid or vice versa and from one plasmid to anther plasmid as well.
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