Molecular mechanisms of resistance to commonly used non-betalactam drugs in Streptococcus pneumoniae.
This article reviews the molecular mechanisms of resistance to fluoroquinolones, erythromycin, chloramphenicol, tetracycline, and trimethoprim-sulfamethoxazole in Streptococcus pneumoniae. Resistance to fluoroquinolones primarily involves mutations in the DNA gyrase gene, gyrA, and in the topoisomerase IV genes, parC and parE, although in vitro studies have indicated that some strains may use an efflux mechanism for resistance to certain fluoroquinolones. Ciprofloxacin resistance results from initial and necessary mutations in ParC leading to low-level resistance and subsequent mutations in GyrA leading to high-level resistance. Sparfloxacin resistance results from initial mutations in GyrA, with ParC mutations occurring subsequently. A single amino acid substitution in ParE has also been associated with low-level resistance in S pneumoniae. Two mechanisms have been described for resistance to erythromycin. Coresistance to macrolides, lincosamides, and streptogramin B type antibiotics is a result of modification of the ribosome through methylation of an adenine residue in domain V of the 23S rRNA. This methylation is encoded by the methylase gene, ermAM. Resistance only to 14-and 15-membered macrolides is a result of efflux of the antibiotic from the cell, encoded by the gene, mefE, in S pneumoniae, and appears to be rapidly emerging as the predominant mechanism of resistance to erythromycin in many countries. The production of chloramphenicol acetyltransferase, an enzyme capable of catalyzing the conversion of chloramphenicol to its nonfunctional 1-acetoxy, 3-acetoxy, and 1,3-diacetoxy derivatives, leads to chloramphenicol resistance in S pneumoniae. Chloramphenicol acetyltransferase is encoded by a cat gene identical to the cat gene from the Staphylococcus aureus plasmid, pC194. Tetracycline resistance occurs through ribosomal protection encoded by the genes tet(M) and tet(O). It is possible that the Tet(M) and Tet(O) proteins cause tetracycline to be released from the ribosome, although the precise mechanism remains unclear. Resistance to trimethoprim is mediated through a single amino acid substitution in the chromosomal dihydrofolate reductase gene of S pneumoniae, which is thought to disrupt the bond with trimethoprim without affecting the action of the dihydrofolate reductase. Sulphonamide resistance appears to result from repetitions of one or two amino acids in the chromosomal dihydropteroate synthase. Although resistance exists to nearly all antimicrobial agents used in the treatment of S pneumoniae infections, ongoing research into new or alternative therapies is encouraging.
Widdowson
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CA
MRC/SAIMR/WITS Pneumococcal Diseases Research Unit, South African Institute for Medical Research, Johannesburg.
Klugman
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D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002415:Cats; D018432:Drug Resistance, Multiple; D004917:Erythromycin / Q000494:pharmacology*; D024841:Fluoroquinolones; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008967:Molecular Biology; D010406:Penicillins / Q000008:administration & dosage; D011008:Pneumococcal Infections / Q000188:drug therapy; D012680:Sensitivity and Specificity; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000302:isolation & purification; D013752:Tetracycline / Q000494:pharmacology*; D014295:Trimethoprim / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D005493:Folic Acid Antagonists; D010406:Penicillins; D004917:Erythromycin; D014295:Trimethoprim; D013752:Tetracycline