Origin of resistance genes

At the time antibiotics were first introduced, the biochemical and molecular basis of resistance was not known. Bacteria collected between 1914 and 1950 (the Murray Collection) were found to be completely sensitive to antimicrobial agents, including sulfanamides that had been introduced in the mid-1930s [38]. However, they contained a large number of plasmids capable of conjugative transfer. Antimicrobial resistance was reported in the early 1940s in streptococci, gonococci, and staphylococci. Recognition of the mutation of the target genes for streptomycin in M tuberculosis soon after its introduction led to the concept of multidrug therapy for tuberculosis.

To understand the evolution and dissemination of antimicrobial resistance genes, it is important to appreciate the rapidity of bacterial multiplication and the constant exchange of bacteria among human, environmental, animal, and agricultural sources throughout the world. Evidence supports the notion that the antimicrobial resistance determinants were not derived from the currently observed bacterial hosts of the resistance plasmids [39-41]. Because the evolutionary time-frame is only 60 years, it is difficult to create a model in which mutations from common ancestral genes alone would have led to the current level of antimicrobial resistance. It is more likely that they were derived from a large and diverse gene pool, presumably already present in environmental bacteria. Many fungi and bacteria that produce antibiotics possess determinants of resistance that are similar to those found in pathogenic bacteria. Could this be nature's way of putting us in our place? It has been reported that commercial antibiotic preparations contain DNA including antibiotic resistance gene sequences from the producing bacteria [42]. Gene exchange occurs in soil or, more likely, in the gastrointestinal tract of humans and animals. This is where the selection pressure by antimicrobial agents is the heaviest. The injudicious use of antimicrobial agents in medical practice is certainly responsible for that selection pressure. However, agricultural, veterinary, and lately household use of antibacterial agents contributes significantly to resistance in human pathogens. The search for newer antimicrobial agents with different mechanisms of action is ongoing and most likely will only result in temporary improvement in the antimicrobial resistance scenario, as has been seen in the past 6 decades.

Table 1

Common mechanisms of resistance among bacteria and genetic basis

Mechanisms of resistance

Antibiotic class

Enzymatic inhibition pS-lactamases

Group 1 — cephalosporin pi-lactam hydrolyzing not inhibited by CA

Group 2a — penicillanases inhibited pi-lactam by CA

Group 2bN — broad spectrum not pi-lactam inhibited by CA

Group 2b — extended broad pi-lactam spectrum

Group 2c — carbenicillinases, pi-lactam oxacillinases

Group 2e — cephalosporins inhibited pi-lactam by CA


Group 3 — metalloenzymes Group 4 — penicillinases not inhibited by CA Acetyltransferases, adenyltransferases, phosphotransferases

Aminoglycosides pi-lactam pi-lactam

Chlororamphenicol acetyltransferases



Example micro-organisms

Chromosomal, produce ß-lactamases constitutively Plasmid mediated

Plasmid, chromosomal

Plasmid mediated

Plasmid, chromosomal Plasmid, chromosomal Plasmid, chromosomal

Plasmid, chromosomal Plasmid, chromosomal

Plasmid mediated except Enterococcus faecium

Enterobacter, Klebsiella, and Citrobacter spp resistant to third-generation cephalosporins

Staphylococcus aureus resistant to penicillin but sensitive to amoxicillin CA Escherichia coli resistant to amoxicillin CA

Plasmodium aeruginosa and Klebsiella spp resistant to ceftazidime and other third-generation cephalosporins P aeruginosa resistant to carbenicillin and piperacillin Nocardia, Actinomadura, Bacillus, and

Mycobacterium spp Stenotrophomonas maltophilia susceptible to ticarcillin-CA; bacteroides spp resistant to ß-lactams

S maltophilia resistant to carbapenems Ralstonia (Burkholderia) cepacia resistant to ß-lactams

Enterococci and gram-negative bacilli highly resistant to ß-lactams

Esterases, phosphotransferases Permeability-uptake

Porin channels Drug efflux

Target site alteration Altered penicillin-binding protein

Altered cell wall oligopeptide

Altered ribosomal target

Competitive inhibition by overproduction of P-aminobenzoic acid or altered dihydropteroate synthetase Auxotrophs—utilization of alternative

Macrolides, streptogramins

(dalfopristin) ß-lactam, aminoglycosides, and macrolides

Quinolones, tetracycline, chloramphenicol, and ß-lactam


Tetracycline, macrolides and aminoglycosides, streptogramins (quinupristin), oxazolidinone Sulfonamides


Plasmid Chromosomal

ß-lactam and carbapenems Chromosomal

Tet gene for tetracycline resistance—plasmid or chromosomal

Plasmid mediated in S aureus; mosaic genes in penicillin-resistant Streptococcus pnumoniae vanA and vanB-

transferable plasmid;

vanC-contitutive plasmid

Plasmid mediated; cross-resistance common

Enterobacteriaceae highly resistant

P aeruginosa resistant to ß-lactams; gramnegative bacteria, enterococci, and staphylococci resistant to aminoglycosides

P aeruginosa, S maltophilia, and Aeromonas spp

P aeruginosa and S aureus

S aureus resistant to methicillin; Spneumoniae resistant to penicillin

Enterococci resistant to vancomycin and teicoplanin

Enterococci, E coli, and Neisseria gonorrhoeae resistant to streptomycin; S aureus, streptococci, and enterococci spp resistant to macrolides

E coli, S aureus, and Neisseria spp

Enterococci growth requirements

Abbreviation: CA, Clavulanic acid.

Adapted from Virk A, Steckelberg JM. Symposium on antimicrobial agents. Part XVII. Clinical aspects of antimicrobial resistance. Mayo Clin Proc 2000;75(2):200; with permission.

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