Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam–Daptomycin Synergy

Abstract

fThe activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of ␤-lactam antibiotics. This effect is more pronounced with ␤-lactam antibiotics that exhibit avid binding to penicillin binding protein 1 (PBP1). Here, we present evidence that PBP1 has a significant role in responding to DAP-induced stress on the cell. Expression of the pbpA transcript, encoding PBP1, was specifically induced by DAP exposure whereas expression of pbpB, pbpC, and pbpD, encoding PBP2, PBP3, and PBP4, respectively, remained unchanged. Using a MRSA COL strain with pbpA under an inducible promoter, increased pbpA transcription was accompanied by reduced susceptibility to, and killing by, DAP in vitro. Exposure to ␤-lactams that preferentially inactivate PBP1 was not associated with increased DAP binding, suggesting that synergy in the setting of anti-PBP1 pharmacotherapy results from increased DAP potency on a per-molecule basis. Combination exposure in an in vitro pharmacokinetic/pharmacodynamic model system with ␤-lactams that preferentially inactivate PBP1 (DAP-meropenem [MEM] or DAP-imipenem [IPM]) resulted in more-rapid killing than did combination exposure with DAPnafcillin (NAF) (nonselective), DAP-ceftriaxone (CRO) or DAP-cefotaxime (CTX) (PBP2 selective), DAP-cefaclor (CEC) (PBP3 selective), or DAP-cefoxitin (FOX) (PBP4 selective).Compared to ␤-lactams with poor PBP1 binding specificity, exposure of S. aureus to DAP plus PBP1-selective ␤-lactams resulted in an increased frequency of septation and cell wall abnormalities. These data suggest that PBP1 activity may contribute to survival during DAP-induced metabolic stress. Therefore, targeted inactivation of PBP1 may enhance the antimicrobial efficiency of DAP, supporting the use of DAP-␤-lactam combination therapy for serious MRSA infections, particularly when the ␤-lactam undermines the PBP1-mediated compensatory response.

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…Support for this hypothesis comes from recent data, which demonstrate that fosfomycin appears to reduce PBP1 expression in S. aureus (10). PBP1 expression is increased with daptomycin exposure and is believed to be important in the bacterial compensatory response in response to peptide-induced injury (46). Thus, either pharmacologic antagonism of PBP1, as seen with beta-lactam antibiotics, or compromising expression of key compensatory proteins like PBP1 by fosfomycin may be a foundation for increasing daptomycin-mediate bacterial killing efficiency.…”

Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

“…Previously, an affinity for certain penicillin-binding proteins (PBPs) has been demonstrated to predict an enhancement of DAP activity, with activity against PBP 1 in staphylococci and PBP 5 in enterococci being important (23,40,(42)(43)(44). The most recent data available suggest that the synergy achieved with the carbapenems ertapenem and imipenem, which are selective for PBP 1, in combination with DAP is superior to that achieved when DAP is used in combination with other beta-lactams, including NAF, which possesses nonselective activity against PBPs (44).…”

Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus

“…We previously observed that DAP-mediated sensitization to ␤-lactams occurred with those ␤-lactams that preferentially target PBP 1 or PBP 2, including NAF (PBP 1, PBP 2), IPM (PBP 1), and CTX (PBP 2), whereas no changes were observed with ␤-lactams targeting PBP 4, such as cefoxitin (FOX), or PBP 3, such as cefaclor (CEC) (8,21,22). Similar effects were observed in other in vitro-selected DAP r mutants obtained from DAP s CB1631 (DAP r CB1631 mutants) and CB5011 (DAP r CB5011 mutants) (8).…”