Table 2 Reported mechanisms of drug resistance for various antibiotics

Beta-lactam antibiotics

Penicillin,

Cephalosporin,

Imepenam.

a) Enzyme destruction

Destruction of the beta-lactam ring of antibiotic molecule.

b) Mutation of PBPs

Methicillin resistance is due to the modification at allosteric binding site of PBPs.

c) Down regulation of porins

Diminished the transportation of polar antibiotics into the bacterial cell. Pseudomonas aeruginosa, Klepsiela pneumonia resistant to imepenam

Aminoglycosides

Streptomycin,

Kanamycin,

Gentamycin

a) Ribosomal mutation

Mutation of bacterial A site on 16s RNA of 30S ribosome (Mycobacterium resistance to Streptomycin)

b) Destruction by aminoglycoside metabolizing enzyme (AME)

There are three major enzymes, AACs (AG N-N acyltransferase), ANTs (AG O – Nucleotidyl transferase, APHs (AG O – phosphotransferase). Among all, AACs are more common in Gram-negative bacteria.

c) Cell membrane modification

In case of OM modification, the cell membrane is modified by incorporation of positively charged 4-amino-4-deoxy-L-arabinose, which repulses the polycationic aminoglycoside.

d) Efflux pump

The efflux pump which decreases the intracellular concentration.

Fluoroquinolones

Ciprofloxacin,

Ofloxacin,

Levofloxacin

a) Decreased drug update

It may be due to the alteration in OM and activation of efflux pump. Both are common in Gram-negative bacteria, but S. aureus shows drug resistance through an efflux mechanism alone.

b) Altered target

The two enzymes, which bind with fluoroquinolones, undergo mutation viz., DNA gyrase (Gram-negative bacteria) and topoisomerase IV (Gram-positive bacteria).

c) Qnr protein mediated

Qnr protein is due to expression of mutation that protects the nucleic acid enzyme from binding to fluoroquinolones.

Glycopeptides

Vancomycin

Mutation in cell wall precursor component by replacement of C-terminal D-alanine with D-lactate or D-serine

There are six types of resistance (Van A, Van B, Van C, Van D, Van E and Van G) among these ABDEG are acquired resistance whereas C is intrinsic. Van A and B are located at plasmid where the rest of them located in the chromosome.

Macrolides/lincosamides

Erythromycin,

Oleondomycin

a) Target site modification by methylation (Streptococci) at 23s rRNA of 50S ribosome.

There are nearly 40 erm genes are found among them erm A, B, C, F is reported in pathogenic microbes like Streptococcus, Enterococcus and Bacteroids

b) Efflux pumps

In Gram-negative bacteria, it is mediated by ABC (ATP-binding cassette transporter) and MFS (major facilitator super-family). In case of Gram-negative bacteria, it is mediated by chromosomally encoded pumps.

c) Drug inactivation of enzymes

The enzyme like esterase and phosphoesterase (Enterococci) destroys erythromycin, 14, 15 member macrolides. But these enzymes do not destroy lincosamides.

Sulphonamides

Sulfomethoxazole

Sulfodoxine

Sulfodimidine

Mutation of DHPS enzyme (Dihydropteroate synthase) responsible for binding of sulphonamide.

Mediated by sul1 and sul2 genes, which are mediated by horizontal transfer (plasmid coded). Trimethoprim shows resistance via plasmid borne resistance.

Tetracyclines

Doxycycline,

Minocycline,

Glycylcycline

a) Tetracycline efflux pump (efflux or TET proteins)

Efflux resistant genes are mediated by plasmids. Gram-positive efflux is regulated by an attenuation mechanism whereas Gram-negative efflux is mediated by repressor that binds with tetracycline.

b) Drug modification

Chemical modification tetracycline by a cytoplasmic protein in presence of NADPH and Oxygen. But still it is unclear.

c) Target mutation

Modification of 30S ribosome, which is responsible for the attachment of aminoacyl tRNA to RNA ribosome.

d) By specific ribosome protection protein (Tet (O), a translational GTPase)

There are nine ribosomal protection proteins reported that protect the ribosome from tetracyclines. This is mediated by both plasmid and self-transmissible chromosomal elements (Conjugative transposons).