Simultaneous breakdown of multiple antibiotic resistance mechanisms in S. aureus

In previous studies, the oligo‐acyl‐lysyl (OAK) C 12(ω7) K‐β 12 added to cultures of gram‐positive bacteria exerted a bacteriostatic activity that was associated with membrane depolarization, even at high concentrations. Here, we report that multidrug‐resistant Staphylococcus aureus strains, unlike other gram‐positive species, have reverted to the sensitive phenotype when exposed to subminimal inhibitory concentrations (sub‐MICs) of the OAK, thereby increasing antibiotics potency by up to 3 orders of magnitude. Such chemosensitization was achieved using either cytoplasm or cell‐wall targeting antibiotics. Moreover, eventual emergence of resistance to antibiotics was significantly delayed. Using the mouse peritonitis‐sepsis model, we show that on single‐dose administration of oxacillin and OAK combinations, death induced by a lethal staphylococcal infection was prevented in a synergistic manner, thereby supporting the likelihood for synergism to persist under in vivo conditions. Toward illuminating the molecular basis for these observations, we present data arguing that sub‐MIC OAK interactions with the plasma membrane can inhibit proton‐dependent signal transduction responsible for expression and export of resistance factors, as demonstrated for β‐lactamase and PBP2a. Collectively, the data reveal a potentially useful approach for overcoming antibiotic resistance and for preventing resistance from emerging as readily as when bacteria are exposed to an antibiotic alone.—Kaneti, G., Sarig, H., Marjieh, I., Fadia, Z., Mor, A., Simultaneous breakdown of multiple antibiotic resistance mechanisms in S. aureus . FASEB J. 27, 4834‐4843 (2013). www.fasebj.org