Antimicrobial peptide exposure and reduced susceptibility to daptomycin: insights into a complex genetic puzzle.

Adequate antibiotic treatment of bacterial infections is one of the most important problems of our time, not only because of the incessant development of antibiotic resistance, but also because of diminished development of novel antibacterial products. Attention has been focused on this problem by the recent United Nations World Health Day in April 2011, which highlighted antibiotic resistance and issued calls for urgent action by expert scientific panels tasked to establish priorities and solutions [1]. Among the proposals is a call for enhanced understanding of resistance, including mechanisms and means of predicting its emergence. Obtaining this knowledge will clearly affect the prudent use of antibiotics and drive novel antibiotic discovery and development strategies. Cationicantimicrobialpeptides(CAMPs) are compounds of great pharmacologic and biologic interest, especially because they have nonspecific and multiple modes of action, which are believed to thwart or forestall the development of resistance. CAMPs are widely distributed in nature and constitute key effectors in innate immune responses to infection in organisms ranging from mammals to plants. CAMPs share cationic and amphipathic properties but vary in sequence, secondary structures, and size. Their antimicrobial activity is initiated through a nonspecific electrostatic interaction with the anionic heads of membrane phospholipids, leading to membrane depolarization or pore formation. Increasing evidence indicates that some CAMPs are probably internalized, leading to interaction with intracellular targets, suggesting that membrane damage alone might not be the principal antimicrobial mechanism of CAMPs [2–4]. Although CAMPs are considered promising candidate templates for development of novel antimicrobials, it has recently been shown that bacteria are capable of adapting and resisting CAMPs, perhaps because of co-evolution within their host. These resistance mechanisms include production of peptidases and proteases that degrade antimicrobial peptides, production of compounds that inhibit the action of CAMPs, and reduction of net anionic charge of the bacterial cell envelope [5]. Daptomycin, a calcium-dependent antimicrobial lipopeptide, is used to treat certain skin infections resulting from various gram-positive organisms and especially bloodstream infections due to Staphylococcus aureus. In some respects, daptomycin resembles CAMPs because of its peptide content, charge, and mode of action targeting membrane function. S. aureus strains displaying reduced susceptibility to daptomycin have been observed both in vivo and in vitro [6–8]. Of interest, cross-resistance between daptomycin and other CAMPs that target the bacterial cell membrane has also been reported. These studies suggest that exposure to daptomycin could confer reduced susceptibility to endovascular host defense antimicrobial peptides, notably thrombin-induced platelet microbicidal proteins (tPMPs) and human neutrophil peptide-1 (hNP-1) [9]. A natural extension of these findings concerning crossresistance evolution is to consider the consequences of the reciprocal order of exposure. In this issue of the Journal, Mishra and coworkers address this important aspect by asking whether there is a potential priming role of preexposure to endovascular host cationic peptides in the development of early stages of bacterial resistance to daptomycin. Their study relied on a carefully selected set of 47 independent methicillin-resistant S. aureus (MRSA) strains collected from Received and accepted 29 June 2012; electronically published 16 August 2012. Correspondence: Daniel P. Lew, Prof., Service of Infectious Diseases, University Hospital and Medical School of Geneva, 4 Rue Gabrielle Perret Gentil, CH 1205, Geneva, Switzerland ([email protected]). The Journal of Infectious Diseases 2012;206:1153–6 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jis485