MED-NERD

Antibiotic resistance mechanisms

Antimicrobial resistance (AMR) is defined as the ability of microorganisms to grow at high concentrations of antibiotics resulting in treatment failure. AMR leads to increased morbidity and mortality. MIC is the minimum inhibitory concentration of antibiotic that can be effective against the microorganism. Resistant bacteria can grow and multiply at antibiotic concentrations that are fatal to other microorganisms of the same species. AMR can be acquired by mutations in genes or horizontal transfer of chromosomal genes or plasmids.

Triclosan is an antimicrobial substance that acts by targeting the enoyl‐ACP reductase enzyme and inhibiting fatty acid synthesis. However, triclosan is ineffective against Pseudomonas aeruginosa due to the presence of insensitive homologue of fabI (enoyl‐ACP reductase), fabV encoding an enzyme that is not inhibited by triclosan.
Gram-negative bacteria, which are less permeable than Gram-positive ones,  show intrinsic resistance to different antimicrobial agents including the cell wall active glycopeptide vancomycin due to the inability to cross the outer bacterial membrane.
Staphylococcus aureus is a Gram-positive organism that rapidly acquires antibiotic resistance by obtaining specific genetic modifications through mutations or gene transfer leading to epidemic infections.

The molecular mechanisms of developing antibiotic resistance include:

• Reducing intracellular antibiotic concentrations.
• Modifying the antibiotic target.
• Inactivating antibiotic.

Reducing intracellular antibiotic concentrations:

Decreasing intracellular concentrations of antibiotics can be through decreasing bacterial cell membrane permeability. Escherichia coli, carbapenem‐resistant Enterobacter species, Klebsiella pneumoniae and other Gram‐negative organisms decrease cell membrane permeability through mutated porins or reduced porin expression on the cell membrane.

Increasing the efflux of antibiotics is another method of decreasing intracellular concentrations of antibiotics and therefore, antibiotic resistance through substrate-specific or Multiple drug resistance (MDR) efflux pumps.
Some MDR efflux pump genes can be transferred between bacteria through plasmids. An example of this are genes coding for novel tripartite resistance nodulation division (RND) pump and genes encoding for the antibiotic‐targeting enzyme New Delhi metallo‐β‐lactamase 1 (NDM‐1) were found to be carried on a plasmid therefore, antimicrobial resistance can be transferred between bacteria. P. aeruginosa and S. aureus, which overexpress drug pumps, were isolated from patients with systemic infections.

Modifying the antibiotic target:

Ineffective target binding and inhibiting antibiotics can be achieved through conformational changes due to spontaneous mutations or post‐translational modifications of an antibiotic target molecule. In S.aureus, resistance to ciprofloxacin occurs due to single amino acid changes near the active site tyrosine of the bacterial type II topoisomerase enzymes, DNA gyrase GyrA or DNA topoisomerase IV ParC, which is known as quinolone resistance determining region (QRDR). If Rifampicin is used alone as a monotherapy, resistance develops rapidly in methicillin‐resistant S. aureus (MRSA) through mutations in the gene encoding for the β‐subunit of the DNA‐dependent RNA polymerase (RpoB) leading to the decreased affinity for rifampicin and therefore, rapidly developing resistance.

Inactivating antibiotic:

Resistance can occur through direct modifications of antibiotics. Transfer of chemical groups to vulnerable sites, inhibiting target binding, and direct destruction by hydrolysis can cause antibiotic resistance.

Adding a chemical group (e.g., ribitoyl, nucleotidyl, phosphate, and acyl groups) leads to steric hindrance and inactivation of antibiotics. Aminoglycosides are examples of this antibiotic inactivation mechanism due to the large molecules of aminoglycosides with multiple exposed hydroxyl and amide groups. In China, an isolated genomic island from chickens found in Campylobacter coli harbours genes for six aminoglycoside‐modifying enzymes showing resistance to aminoglycosides, including gentamicin.

 The evolution of a wide range of enzymes that can inactivate antibiotics has occurred due to the development of new derivatives of already-known antibiotic classes. An example of this is that early β‐lactamases were active against the 1st‐generation β‐lactams, followed by extended‐spectrum β‐lactamases (ESBLs) that can hydrolyse extended‐spectrum oxyimino cephalosporins (e.g., cefmenoxime, cefuroxime, ceftriaxone, and cefotaxime).

 Increasing the use of carbapenems and increasing the number of bacteria carrying ESBL genes resulted in the emergence of carbapenemase‐producing strains. A variety of β‐lactams can be inactivated by carbapenemases such as extended‐spectrum cephalosporins, and many carbapenemase‐genes being carried on plasmids and found in K. pneumoniae, Acinetobacter baumannii, Enterobacteriaceae, and P. aeruginosa.

References:

(1) Huemer M, Mairpady Shambat S, Brugger SD, Zinkernagel AS. Antibiotic resistance and persistence-Implications for human health and treatment perspectives. EMBO Rep. 2020 Dec 3;21(12):e51034.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726816/

(2) Ghosh D, Veeraraghavan B, Elangovan R, Vivekanandan P. Antibiotic Resistance and Epigenetics: More to It than Meets the Eye. Antimicrob Agents Chemother. 2020 Jan 27;64(2):e02225-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985748/

(3) Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. P T. 2015 Apr;40(4):277-83.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/