Cross-resistance – A single resistance mechanism that makes a species or strain resistant to all the structurally or functionally related antibiotics.
Co-resistance – Several different resistance mechanisms that make a bacterium resistant to unrelated drugs. The resistance mechanisms are essentially present on the same plasmid, transposon or integron.
Natural / Innate resistance:
- Inaccessibility of the drug into the bacterial cell eg., outer membrane of gram negative bacteria (serves as an additional protection layer); thick, impermeable cell wall of Mycobacteria due to mycolic acids
- Expulsion of drugs due to chromosomally encoded ABC transporters eg., in aeruginosa
- Chromosomal production of enzymes that inactivate drugs making such bacteria naturally resistant to such drugs eg., beta-lactamase produced by some members of Enterobacteriaceae
- Lack of cellular target eg., absence of cell wall in Mycoplasmas, hence resistant to cell wall synthesis inhibitors
- Lack of affinity of the drug for the target
Acquired resistance:
- Spontaneous mutations that can be vertically transmitted to daughter cells
- Horizontal gene transfer by conjugation, transformation or transduction
The ways by which multidrug resistance arises in bacteria are:-
- Prevent the penetrance of drugs – genetic mutations that lead to changes in penicillin binding protein, decrease in cell permeability leads to sulfonamide resistance, Mycobacteria possess mycolic acids in their cell wall making them resistant to most water-soluble drugs.
- Pump drugs out of the cell – Many pathogens utilize efflux pumps (ABC transporters), a type of membrane transport protein, that expel all sorts of drugs. Hence, they are called multidrug resistance pumps. Some pathogens like E.coli, S.aureus, P.aeruginosa use drug/proton antiporters to expel out drugs.
- Inactivation of drugs by chemical modification – hydrolysis of beta lactam ring of penicillin by penicillinase enzyme, chloramphenicol is modified by acetylation by chloramphenicol acetyltransferase, aminoglycosides could be modified by acetylation of amino group or phosphorylation or adenylation of hydroxyl groups.
- Modification of target enzyme or cellular structure making it no longer susceptible to the drug – alteration of 23S rRNA (a part of 50S ribosomal unit) making bacteria resistant to erythromycin and chloramphenicol, Enterococci change terminal D-Alanine-D-Alanine in their peptidoglycan to D-Alanine-D-Lactate getting resistant to penicillin.
- Use of alternate pathways to bypass the sequence inhibited by the drug
- Increase the production of target metabolite
- Target replacement – Bacteria could make a fake target that binds to the antibiotics leaving the real target free so that the antimicrobials are now rendered inactive.
Genes for drug resistance could be present on chromosomes, plasmids or transposons. These genes are often present on mobile genetic elements so that they can transferred between genus, species and strains by horizontal gene transfer. Resistance due to spontaneous mutations are rare. However, when a patient is treated exhaustively with antibiotics, some resistant mutants arise and survive due to their competitive advantage over non-resistant strains.
Plasmids called R plasmids (resistance plasmids) carry multiple drug resistance genes that encode enzymes such as penicillinase, chloramphenicol or aminoglycoside acetyltransferase. These plasmids make bacteria resistant to a whole lot of drugs. Once a bacterial cell possesses an R plasmid, it may be transferred to other cells rapidly by conjugation, transformation or transduction.
Certain transposons contain resistance genes for several drugs. They are found in both gram positive and negative bacteria eg. Tn5 (kanamycin, bleomycin, streptomycin). Such genes on composite transposons can move quickly between plasmids and through a bacterial population. Often several resistance genes are carried as gene cassettes in association with a genetic element called integron. Integron contains an integrase gene and sequences for site-specific recombination.
Conjugative transposons also carry drug resistance genes. Because they move between cells by conjugation, they are effective in spreading resistance.
Some measures to combat this intimidating problem are:-
- Complete the antibiotic regimen as well as follow the timings of the doses religiously as prescribed by the doctor in case of infectious diseases otherwise one shall be giving the pathogens an interim period wherein they can undergo spontaneous mutations and emerge as resistant to the drug.
- The drug may be given in high enough concentrations to destroy susceptible bacteria and the spontaneous mutant that might arise during the treatment.
- A combination of 2 or 3 drugs may be given in the hope that each will prevent the emergence of resistant bacteria to the other.
- Broad spectrum drugs should be given only when absolutely necessary like under life-threatening situations. The pathogen must be identified by lab diagnosis, AST performed and a proper narrow spectrum drug specific to the pathogen must be employed.
- Search for new antibiotics that these bacteria have not encountered ever before.
- Develop efflux pump inhibitors that would prevent multidrug resistance.
- Find new drug targets in these microbes.