title: Combining the FtsZ-Targeting Prodrug TXA709 and the Cephalosporin Cefdinir Confers Synergy and Reduces the Frequency of Resistance in Methicillin-Resistant Staphylococcus aureus.
abstract: Combination therapy of bacterial infections with synergistic drug partners offers distinct advantages over monotherapy. Among these advantages are (i) a reduction of the drug dose required for efficacy, (ii) a reduced potential for drug-induced toxicity, and (iii) a reduced potential for the emergence of resistance. Here, we describe the synergistic actions of the third-generation oral cephalosporin cefdinir and TXA709, a new, FtsZ-targeting prodrug that we have developed with improved pharmacokinetics and enhanced in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA) relative to earlier agents. We show that the active product of TXA709 (TXA707) acts synergistically with cefdinir in vitro against clinical isolates of MRSA, vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), and linezolid-resistant S. aureus (LRSA). In addition, relative to TXA707 alone, the combination of TXA707 and cefdinir significantly reduces or eliminates the detectable emergence of resistance. We also demonstrate synergy in vivo with oral administration of the prodrug TXA709 and cefdinir in mouse models of both systemic and tissue (thigh) infections with MRSA. This synergy reduces the dose of TXA709 required for efficacy 3-fold. Viewed as a whole, our results highlight the potential of TXA709 and cefdinir as a promising combination for the treatment of drug-resistant staphylococcal infections.
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Malvika
authors.initials: M
authors.lastname: Kaul
authors.affiliation: TAXIS Pharmaceuticals, Inc., Monmouth Junction, New Jersey, USA Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
authors.forename: Lilly
authors.initials: L
authors.lastname: Mark
authors.affiliation: TAXIS Pharmaceuticals, Inc., Monmouth Junction, New Jersey, USA Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Parhi
authors.affiliation: Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: LaVoie
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA pilchds@rwjms.rutgers.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pilch
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism; D000077525:Cefdinir; D002511:Cephalosporins / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004357:Drug Synergism; D000069349:Linezolid / Q000494:pharmacology; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance / Q000235:genetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D011355:Prodrugs; D014640:Vancomycin; D000077525:Cefdinir; D000069349:Linezolid; D008712:Methicillin