Article Figures & Data
Figures
- FIG. 1.
History of antibiotic discovery and concomitant development of antibiotic resistance. The dark ages, the preantibiotic era; primordial, the advent of chemotherapy, via the sulfonamides; golden, the halcyon years when most of the antibiotics used today were discovered; the lean years, the low point of new antibiotic discovery and development; pharmacologic, attempts were made to understand and improve the use of antibiotics by dosing, administration, etc.; biochemical, knowledge of the biochemical actions of antibiotics and resistance mechanisms led to chemical modification studies to avoid resistance; target, mode-of-action and genetic studies led to efforts to design new compounds; genomic/HTS, genome sequencing methodology was used to predict essential targets for incorporation into high-throughput screening assays; disenchantment, with the failure of the enormous investment in genome-based methods, many companies discontinued their discovery programs. Other milestones in this history include the creation of the FDA Office of New Drugs after the thalidomide disaster led to stricter requirements for drug safety, including the use of antibiotics. This slowed the registration of novel compounds. Before antibiotics were discovered, Semmelweis advocated hand washing as a way of avoiding infection; this practice is now strongly recommended as a method to prevent transmission.
- FIG. 2.
Numbers of unique β-lactamase enzymes identified since the introduction of the first β-lactam antibiotics. (Up-to-date numbers are courtesy of Karen Bush.)
- FIG. 3.
Worldwide distribution of different classes of CTX-M β-lactamases (first identified in 1989). (Reprinted from reference 71 by permission of Oxford University Press.)
- FIG. 4.
Dissemination of antibiotics and antibiotic resistance within agriculture, community, hospital, wastewater treatment, and associated environments. (Adapted from reference 49 and reference 83a with permission of the publishers.)
- FIG. 5.
Integron structure and gene capture mechanism. This figure indicates the basic elements of integrons, as found in bacterial genomes. The structure consists of an integrase (Int) with the Pint and PC promoters in the 3′ end of the gene, with its associated cassette attachment or insertion site (attI). The integrase catalyzes the sequential recombination of circularized gene cassettes into the distal attachment site to create an operon-like arrangement (ant1r, ant2r, and so on) of r genes transcribed from the strong PC promoter (132). Three classes of integrons have been identified that differ in their integrase genes.
Tables
- TABLE 1.
Modes of action and resistance mechanisms of commonly used antibioticsa
Antibiotic class Example(s) Target Mode(s) of resistance β-Lactams Penicillins (ampicillin), cephalosporins (cephamycin), penems (meropenem), monobactams (aztreonam) Peptidoglycan biosynthesis Hydrolysis, efflux, altered target Aminoglycosides Gentamicin, streptomycin, spectinomycin Translation Phosphorylation, acetylation, nucleotidylation, efflux, altered target Glycopeptides Vancomycin, teicoplanin Peptidoglycan biosynthesis Reprogramming peptidoglycan biosynthesis Tetracyclines Minocycline, tigecycline Translation Monooxygenation, efflux, altered target Macrolides Erythromycin, azithromicin Translation Hydrolysis, glycosylation, phosphorylation, efflux, altered target Lincosamides Clindamycin Translation Nucleotidylation, efflux, altered target Streptogramins Synercid Translation C-O lyase (type B streptogramins), acetylation (type A streptogramins), efflux, altered target Oxazolidinones Linezolid Translation Efflux, altered target Phenicols Chloramphenicol Translation Acetylation, efflux, altered target Quinolones Ciprofloxacin DNA replication Acetylation, efflux, altered target Pyrimidines Trimethoprim C1 metabolism Efflux, altered target Sulfonamides Sulfamethoxazole C1 metabolism Efflux, altered target Rifamycins Rifampin Transcription ADP-ribosylation, efflux, altered target Lipopeptides Daptomycin Cell membrane Altered target Cationic peptides Colistin Cell membrane Altered target, efflux ↵ a Adapted from reference 150a with permission of the publisher.
