Affiliation:
1. Biosynexus Incorporated, Gaithersburg, Maryland 20877
Abstract
ABSTRACT
Lysostaphin is under development as a therapy for serious staphylococcal infections. During preclinical development, lysostaphin-resistant
Staphylococcus aureus
variants have occasionally been reported in vitro and in vivo. The acquisition of resistance to this drug, however, leads to a significant increase in β-lactam antibiotic susceptibility, rendering methicillin-resistant
S. aureus
(MRSA) strains functionally methicillin susceptible. In this study, we have demonstrated that the development of lysostaphin resistance by two strains of MRSA also led to a loss of fitness in the variants. Consistent with the mutations found in previously reported lysostaphin-resistant
S. aureus
variants, these two variants had mutations in their
femA
genes, resulting in nonfunctional FemA proteins and, thus, monoglycine cross bridges in the peptidoglycan. The diminished fitness of the lysostaphin-resistant variants was reflected by (i) a reduced logarithmic growth rate, with the variants being outcompeted in cocultures by their wild-type parental strains; (ii) increased susceptibility to elevated temperatures; and (iii) at least fivefold less virulence of the lysostaphin-resistant variants than their wild-type strains in a mouse kidney infection model, with the lysostaphin-resistant variants being outcompeted in coinfections with their wild-type parental strains. During a 14-day serial passage without selective pressure, the lysostaphin-resistant variants failed to develop compensatory mutations which restored their fitness. These results suggest that should lysostaphin resistance due to an alteration in the FemA function emerge in
S. aureus
during therapy with lysostaphin, the resistant variants would be less fit and less virulent, and, in addition, infections with these strains would be easily treatable with β-lactam antibiotics.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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