β-Lactams Increase the Antibacterial Activity of Daptomycin against Clinical Methicillin-Resistant Staphylococcus aureus Strains and Prevent Selection of Daptomycin-Resistant Derivatives

Mehta, Shrenik; Singh, Christopher R.; Plata, Konrad; Chanda, Palas K.; Paul, Abhik; Riosa, Sarah; Rosato, Roberto R.; Rosato, Adriana E.

doi:10.1128/aac.01525-12

Cited by 124 publications

(96 citation statements)

References 49 publications

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“…For all strains, the DAP MIC was lowered in the presence of all of the ␤-lactam antibiotics tested. The DAP MIC for DNS MRSA was decreased to the susceptible range, consistent with prior data (23). The high fC avg s of some ␤-lactam antibiotics alone (piperacillin-tazobactam [TZP], cefepime [FEP], MEM, and CTX) inhibited the growth of certain strains, and therefore, DAP enhancement could not be evaluated.…”

Section: Resultssupporting

confidence: 62%

β-Lactam Antibiotics Targeting PBP1 Selectively Enhance Daptomycin Activity against Methicillin-Resistant Staphylococcus aureus

Berti

Sakoulas

Nizet

et al. 2013

Antimicrob Agents Chemother

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The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of subinhibitory concentrations of antistaphylococcal ␤-lactam antibiotics by an undefined mechanism. Given the variability in the penicillin-binding protein (PBP)-binding profiles of different ␤-lactam antibiotics, the purpose of this study was to examine the relative enhancement of DAP activity against MRSA by different ␤-lactam antibiotics to determine if a specific PBP-binding profile is associated with the ability to enhance the anti-MRSA activity of DAP. We determined that both broad-and narrowspectrum ␤-lactam antibiotics known to exhibit PBP1 binding demonstrated potent enhancement of DAP anti-MRSA activity, whereas ␤-lactam antibiotics with minimal PBP1 binding (cefoxitin, ceftriaxone, cefaclor, and cefotaxime) were less effective. We suspect that PBP1 disruption by ␤-lactam antibiotics affects pathways of cell division in S. aureus that may be a compensatory response to DAP membrane insertion, resulting in DAP hypersusceptibility. The presence of subinhibitory concentrations of ␤-lactam antibiotics has been shown to increase daptomycin (DAP) activity against both DAP-susceptible and DAP-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) strains (1, 2). The mechanisms of this are not fully understood, but it has been attributed to a ␤-lactam-induced increase in the binding of DAP to bacterial cell membranes (3, 4). These observations fall in line with the observed DAP-␤-lactam "seesaw effect" whereby S. aureus frequently gains susceptibility to ␤-lactams upon the acquisition of the DNS phenotype (5). Collectively, these in vitro observations have been translated to antimicrobial therapy combinations to successfully manage difficult-to-treat MRSA infections (2, 3, 5, 6).Most in vivo studies have focused on three antistaphylococcal ␤-lactams, oxacillin, nafcillin (NAF), and ceftaroline, the latter because of its unique anti-MRSA properties among the ␤-lactam classes. However, no studies have compared the relative differences among the various ␤-lactam classes in their DAP-potentiating properties at therapeutically relevant concentrations.The potentiation of DAP activity obtained by the addition of a ␤-lactam antibiotic may provide a straightforward way to enhance anti-MRSA therapy against both DAP-susceptible and DNS MRSA. Achieving a bacteriostatic DAP area under the concentration-time curve (AUC)/MIC ratio against S. aureus (438 Ϯ 67) is challenging at a normal dose of 6 mg/kg (AUC ϭ 705 Ϯ 67) when the organism's DAP MIC is 2 g/ml or greater (7). Dose escalation to 8 or 10 mg/kg improves the likelihood of attaining this target parameter against strains with elevated MICs but results in a higher minimum drug concentration in serum (C min ), which has been associated with an increased risk of creatine phosphokinase elevation (8). High-dose DAP therapy is of particular concern in obese patients, where DAP AUCs are reported to be 30% greater than in nonobese matched co...

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Section: Resultssupporting

confidence: 62%

β-Lactam Antibiotics Targeting PBP1 Selectively Enhance Daptomycin Activity against Methicillin-Resistant Staphylococcus aureus

Berti

Sakoulas

Nizet

et al. 2013

Antimicrob Agents Chemother

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“…Many bioactive compounds produced by Streptomyces spp., for example phenolic compounds and antibiotics, have been shown to alter cell surface appearance. Previous observations include wrinkling of the cell surface and cell shrinkage [22,24,25].…”

Section: Discussionmentioning

confidence: 99%

Investigation of antibacterial and anti-cancer activities of Streptomyces sp SRF1 culture filtrate

Sangdee¹,

Buranrat²,

Seephonkai³

et al. 2018

Trop. J. Pharm Res

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“…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). Collectively, these observations suggest that the seesaw effect involves CW modifications.…”

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confidence: 99%

mentioning

confidence: 99%

“…In previous studies, we reported that two DAP r strains, CB5036 and CB5014, with mutations in the central domain of MprF, P314L and S377L, respectively, did not display the DAP-mediated seesaw effect; i.e., their OXA MICs remained the same (512 g/ml) in both strains of pairs of DAP s -DAP r strains (strains CB5035 (8). However, as we described previously, the DAP-OXA combination was still effective against them (8). These strains are called homogeneous MRSA because they express a uniformly high level of ␤-lactam resistance different from that seen in the heterogeneous MRSA strains (e.g., CB1634) whose cell populations are able to express differential levels of resistance and that are mostly associated with lower MICs (1 to 32 g/ml).…”

mentioning

confidence: 99%

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

Renzoni

Kelley

Rosato

et al. 2017

Antimicrob Agents Chemother

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Antimicrobial resistance is recognized as one of the principal threats to public health worldwide, yet the problem is increasing. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most difficult to treat in clinical settings due to the resistance of MRSA to nearly all available antibiotics. The cyclic anionic lipopeptide antibiotic daptomycin (DAP) is the clinical mainstay of anti-MRSA therapy. The decreased susceptibility to DAP (DAP resistance [DAP r ]) reported in MRSA is frequently accompanied by a paradoxical decrease in ␤-lactam resistance, a process known as the "seesaw effect." Despite the observed discordance in resistance phenotypes, the combination of DAP and ␤-lactams has been proven to be clinically effective for the prevention and treatment of infections due to DAP r MRSA strains. However, the mechanisms underlying the interactions between DAP and ␤-lactams are largely unknown. In the study described here, we studied the role of mprF with DAP-induced mutations in ␤-lactam sensitization and its involvement in the effective killing by the DAP-oxacillin (OXA) combination. DAP-OXA-mediated effects resulted in cell wall perturbations, including changes in peptidoglycan insertion, penicillin-binding protein 2 (PBP 2) delocalization, and reduced membrane amounts of PBP 2a, despite the increased transcription of mecA through mec regulatory elements. We have found that the VraSR sensor-regulator is a key component of DAP resistance, triggering mutated mprF-mediated cell membrane (CM) modifications that result in impairment of PrsA location and chaperone functions, both of which are essential for PBP 2a maturation, the key determinant of ␤-lactam resistance. These observations provide for the first time evidence that synergistic effects between DAP and ␤-lactams involve PrsA posttranscriptional regulation of CM-associated PBP 2a.KEYWORDS MRSA, daptomycin, seesaw effect, ␤-lactams, PrsA, ␤-lactams S taphylococcus aureus has a proclivity for developing multidrug resistance (e.g., methicillin-resistant S. aureus [MRSA]), and infections with this pathogen result in enhanced attributable mortality (1). Since its FDA approval in 2003, the cyclic anionic lipopeptide antibiotic daptomycin (DAP), produced by Streptomyces roseosporus (2), has become the clinical mainstay of anti-MRSA therapy due to its potent staphylocidal

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β-Lactams Increase the Antibacterial Activity of Daptomycin against Clinical Methicillin-Resistant Staphylococcus aureus Strains and Prevent Selection of Daptomycin-Resistant Derivatives

Abstract: Methicillin-resistant

Cited by 124 publications

References 49 publications

β-Lactam Antibiotics Targeting PBP1 Selectively Enhance Daptomycin Activity against Methicillin-Resistant Staphylococcus aureus

β-Lactam Antibiotics Targeting PBP1 Selectively Enhance Daptomycin Activity against Methicillin-Resistant Staphylococcus aureus

Investigation of antibacterial and anti-cancer activities of Streptomyces sp SRF1 culture filtrate

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

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