Antibiotic resistance is now considered to be a great curse to the present world. Researcher suspected that millions of people will die due to the rapid emergence of antibiotic resistance by 2050. There are lots of reasons how bacteria become resistant to antibiotics. All the reasons can be narrowed into two part; mutation and horizontal gene transfer. In this context, the last reason belongs to horizontal gene transfer-mediated resistance and most of the other reasons are mutation-mediated resistance.
- Destroying the structure of the antibiotic molecule:
Bacteria secrets certain types of enzymes that break down the structure of the drug. This enzyme destroys the antibiotic molecule by breaking down the amide bond of the β-lactam ring, causing the antibiotics ineffective.
Staphylococci show resistance to penicillin G by producing a β-lactamase enzyme that destroys the antibiotic molecule. Some gram-negative rods also become resistant by producing a β-lactamase enzyme.
CTX-M – a most prevalent plasmid-encoded ESBL (Extended Spectrum β-lactamase) enzyme –is responsible for making E. coli and K. pneumoniae resistant to cephalosporin. New Delhi Metallo β-lactamase (NDM-1) enzyme is one of the most concerning enzyme responsible for drug resistance in K. pneumonia.
AmpC is a class C β-lactamase enzyme that is responsible for cephalosporin resistance in E. cloacae, E. aerogenes, Morganella morganii, , S. marcescens, Providencia sp., P. aeruginosa, and C. freundii.
- Altering the structure of antibiotic molecule chemically:
Both gram-negative and gram-positive bacteria acquire antibiotic resistance by causing chemical modification of antibiotic molecule. They produce acetyltransferase, phosphotransferase, and adenyltransferase enzymes for acetylating, phosphorylating or adenylating the antibiotic molecules respectively. This modification causes steric hindrance that reduces the avidity of the antibiotic molecule for its target, which, in turn, inhibits the effectiveness of the antibiotic molecule.
These enzymes are called aminoglycoside-modifying enzymes (AMEs) as they cause chemical modification of aminoglycosides, an effective antibiotic molecule that suppresses the growth of gram-positive bacteria, aerobic gram-negative bacteria, and mycobacteria by inhibiting protein synthesis. Thus, these bacteria become resistant to aminoglycosides by causing chemical modification of aminoglycosides.
- By changing membrane permeability:
Antibiotics accumulate in the bacteria through the permeable membrane of the bacteria to destroy the bacterial pathogenicities. But bacteria become resistant to these antibiotics by altering their membrane permeability to the antibiotics. Some bacteria shows resistant by making their membrane impermeable to the antibiotics.
Bacteria show resistance to tetracycline and polymyxin by altering their membrane permeability to these antibiotics. As a result, tetracycline and polymyxin can’t pass through the plasma membrane.
- Efflux pumps-mediated resistance:
Efflux pumps system is a mechanism that extrudes toxic substances, and antibiotics, out of the cells. This mechanism plays a vital role in developing bacterial resistance to the antibiotic. Efflux pumps are active transporters, as they use chemicals as their source of energy to perform their function. In gram-negative bacteria, tetracycline resistance is acquired by efflux pumps systems where Tet efflux pumps remove tetracyclines from the cells using proton exchange as their chemical energy source. These efflux pumps encoded by 20 different tet genes are carried by mobile genetic elements. Other MDR efflux pumps that extrude tetracycline are AcrAB-TolC and MexAB-OprM found in Enterobacteriaceae and P. aeruginosa.
RND pumps cause bacterial resistance to tetracyclines, chloramphenicol, some β-lactams, novobiocin, fusidic acid, and fluoroquinolones by pushing these antibiotics out of the cells.
- Changing metabolic pathways:
Antibiotics inhibit the enzymes that are involved in the bacterial metabolic pathway. But bacteria produce altered enzymes to continue their metabolism, and thus perform their pathogenesis and become resistant to antibiotics.
Bacteria become resistant to trimethoprim by producing an altered dihydrofolate reductase enzyme that lacks the binding site for trimethoprim.
Bacteria causes the increased production of p-aminobenzoic acid, increased synthesis of pteridine, and increased production of sulfonamide-resistant dihydropteroate synthetase and thus become resistant to the sulfonamides.
- Altering Structural targets:
Bacteria become resistant to antibiotics by producing an altered structural target for the antibiotics. This resistance may come from a mutation in a gene controlling structural protein or from enzymatic methylation of the ribosome.
The protein P12 on the 30S ribosomal subunit of bacteria is the target site for streptomycin attachment. Alteration in this target site results from a mutation in the gene encoding for P12 protein.
Loss or alteration of PBPs is also the mutations that make bacteria (S. pneumonia and enterococci) resistant to beta-lactam drugs such as penicillin and cephalosporin.
The bacterial resistance to erythromycins due to modification of target site on 50S ribosomal subunit results from enzymatic methylation of 23rRNA of 50S ribosomal subunit
- Protecting Structural targets:
Tetracycline resistance protein Tet(M) and Tet(O) were primarily found in Streptococcus spp. and in Campylobacter jejuni, respectively. But they are now found in wide-range of bacterial species, as in various plasmid and several conjugative transposons.
These proteins are the member of the translation factor superfamily of GTPases and protein synthesis acting as homologs of elongation factors. The proteins show interaction with the ribosome and displacing the tetracycline from its binding site.
K. pneumonia shows the same mechanism of resistance to quinolone by producing quinolone resistance protein.
8. Losing structural targets:
Bacteria become resistant to antibiotics by losing specific target structure for the antibiotics for several generations and never get back these target structure.
Penicillin-susceptible bacteria become resistant to penicillin by converting to cell wall-deficient L forms when penicillin is introduced. Thus, cell wall-destructive antibiotics (penicillin, cephalosporin) can’t interfere with cell wall as the bacteria lack cell walls and thereby can’t inhibit the growth of bacteria. Some bacteria may revert to their previous form by producing cell wall again and become susceptible to the aforementioned antibiotics. If they don’t do that, they remain resistant to these drugs forever.
- Infecting specific sites:
Bacteria infect such a site of host tissue, where bacteria can’t enter the cells of that tissue, or bacteria are excluded from that site of the tissue or are not active.
Salmonella causing enteric fever shows resistance to aminoglycosides such as gentamicins because salmonella are intracellular bacteria and these antibiotics can’t enter the cells.
10. Transfer of antimicrobial transfer gene:
Horizontal gene transfer also plays an important role in the emergence of antibiotic resistance in bacteria. Mobile genetic elements -plasmids, transposons, and integrons- serve as a vehicle to transfer and spread of antimicrobial resistance genes among several bacterial genera of human and animals. Plasmids carrying resistance gene are called R plasmid and is found in both gram-positive and negative bacteria. Qnr plasmids – products of which block the function of ciprofloxacin on purified DNA gyrase and topoisomerase IV – have been found in various types of bacteria such as E. coli, Citrobacter fruendii, Enterobacter species, K. pneumoniae, Providencia stuartii, and Salmonella species over the world.
Transposons are small DNA sequences that can be transferred from one part of the chromosome to another. They transfer a lot of resistance genes from one bacterium to another.
Integrons are also small DNA sequences consist of two conserved segments between which antimicrobial resistance ‘‘gene cassettes’’ can be inserted. Gene cassettes are free circular DNA having 500–1000 base pairs. They can’t be expressed by themselves as they have no promoter region.