Clinical strain of Staphylococcus aureus inactivates and causes efflux of macrolides

Abstract

Searching through a collection of 124 Staphylococcus aureus clinical strains, we found one isolate, strain 01A1032, that inactivates 14- and 16-membered macrolides. The products of inactivation were purified from supernatant fluids of cultures exposed to erythromycin for 3 h and were found to be identical to products of inactivation from Escherichia coli strains that encode either an EreA or EreB esterase. Further, strain 01A1032 was shown to be resistant to azithromycin, a 15-membered macrolide, by an alternate mechanism, efflux. Thus, strain 01A1032 harbors determinants encoding an esterase activity that hydrolyzes 14- and 16-membered macrolides and a macrolide efflux system.

In vitro activities of new ketolide, telithromycin, and eight other macrolide antibiotics against Streptococcus pneumoniae having mefA and ermB genes that mediate macrolide resistance

“…15 Another resistance mechanism is an active efflux pump system for MLS that has been incorporated into cells. The mechanism has been observed in staphylococci, where membrane-binding proteins are encoded by the erpA 31,32 and msrA 28,[33][34][35][36][37] genes.…”

Molecular Mechanisms of Antibiotic Resistance: The Need for Novel Antimicrobial Therapies

“…These typically comprise of six transmembrane-spanning a-helices and two nucleotide-binding domains (NBDs), located on the inner surface of the bacterial cell membrane as sites of ATP hydrolysis (Figure 1.19). Deletion of 42 C-terminal codons from a fragment of S. epidermidis msrA results in loss of the MS resistance phenotype demonstrating the importance of the C-terminal domain [132,133]. All NBDs possess a Walker A motif (P-loop) and a Walker B motif which hydrogen bond extensively with the nucleotide.…”

“…Until recently there had been no reports of esterase activity in Gram-positive organisms; however, strain 01A1032 of S. aureus exhibits esterase activity of 14-and 16-membered macrolides, and also the ability to efflux azithromycin [133]. Ribosomes from strain 01A1032 demonstrated 100% inhibition by erythromycin and azithromycin, ruling out any activity of Erm methylases and ribosomal mutations.…”

“…Polymerase chain reaction (PCR) results gave a PCR product consistent with an msrA-like gene, which implicates an ABC protein in mediating the efflux resistance mechanism. It remains unclear if efflux and enzymatic inactivation are part of one mechanism, act synergistically or are mutually exclusive [133].…”

Mechanisms of bacterial resistance to macrolide antibiotics

“…Three mechanisms of resistance to macrolides in bacteria are known: (1) modification of the antibiotic target, mediated by the so-called erm gene (Table 1); 41 (2) enhanced efflux mediated by the msr, erp, mef, and mre genes ( Table 2); 42,43 (3) inactivation of macrolide antibiotics by erythromycin esterase encoded by the ere or the ere-like gene, 44 by streptogramin B hydrolase encoded by the vgb gene, by macrolide phosphotransferase encoded by the mph gene, and by lincosamide nucleotidyltransferase encoded by the lin gene ( Table 3).…”