The clinical development of FtsZ-targeting benzamide compounds like PC190723 has been limited by poor drug-like and pharmacokinetic properties. Development of prodrugs of PC190723 (e.g., TXY541) resulted in enhanced pharmaceutical properties, which, in turn, led to improved intravenous efficacy as well as the first demonstration of oral efficacy in vivo against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Despite being efficacious in vivo, TXY541 still suffered from suboptimal pharmacokinetics and the requirement of high efficacious doses. We describe here the design of a new prodrug (TXA709) in which the Cl group on the pyridyl ring has been replaced with a CF 3 functionality that is resistant to metabolic attack. As a result of this enhanced metabolic stability, the product of the TXA709 prodrug (TXA707) is associated with improved pharmacokinetic properties (a 6.5-fold-longer half-life and a 3-fold-greater oral bioavailability) and superior in vivo antistaphylococcal efficacy relative to PC190723. We validate FtsZ as the antibacterial target of TXA707 and demonstrate that the compound retains potent bactericidal activity against S. aureus strains resistant to the current standard-ofcare drugs vancomycin, daptomycin, and linezolid. These collective properties, coupled with minimal observed toxicity to mammalian cells, establish the prodrug TXA709 as an antistaphylococcal agent worthy of clinical development. Bacterial resistance has emerged as a global problem. The Centers for Disease Control and Prevention (CDC) have identified methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) as being two major antibiotic resistance threats (1). Typically, MRSA strains are resistant not only to the penicillins but also to other classes of antibiotics, including the tetracyclines, the macrolides, the aminoglycosides, and clindamycin (2-4). Current standard-of-care (SOC) drugs for the treatment of MRSA infections are therefore limited to a few drugs, which include vancomycin, daptomycin, and linezolid (3). However, resistance to these SOC drugs is already on the rise, and the clinical utility of these drugs is likely to diminish in the future (3, 5-9).The bacterial protein FtsZ has been identified as an appealing new target for the development of antibiotics that can be used to treat infections caused by multidrug-resistant (MDR) bacterial pathogens (10-14). The appeal of FtsZ as an antibiotic target lies in the essential role that the protein plays in bacterial cell division (cytokinesis). Furthermore, FtsZ is prokaryote specific with no known eukaryotic homolog. FtsZ self-polymerizes in a GTP-dependent manner to form a ring-like structure (the Z-ring) at midcell that serves as a scaffold for the recruitment and organization of other critical components for proteoglycan synthesis, septum formation, and cell division (15)(16)(17)(18)(19)(20).The substituted benzamide derivative PC190723 has been shown to inhibit bacterial cell div...

Resistant bacterial infections continue to be a challenge for clinicians. Identification of antibiotics with pharmacodynamic advantages may be beneficial in the treatment of these infections. An antibiotic with a longer postantibiotic effect may be able to be administered less frequently resulting in improved adherence. In this study, a new synthetic antimicrobial peptide, LTX-109, demonstrated a more prolonged time for LTX-109 than mupirocin against methicillin-resistant Staphylococcus aureus.

Retapamulin and six other antimicrobial agents were evaluated against 155 methicillin-resistant Staphylococcus aureus (MRSA) isolates, including strains resistant to vancomycin, linezolid, daptomycin, and mupirocin by microdilution tests. Time-kill assays were performed against representative MRSA, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA) isolates. Retapamulin and mupirocin demonstrated MIC 90 s of 0.12 g/ml and 8 g/ml, respectively, with resistance seen in 2.6% and 10% of isolates, respectively. Retapamulin maintained good activity against 94% (15/16) of mupirocin-resistant isolates.

Heteroresistance refers to the presence, within a large population of antimicrobial-susceptible microorganisms, of subpopulations with lesser susceptibilities. Ceftaroline is a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to detect the prevalence of ceftaroline heteroresistance in vitro in a select group of S. aureus strains. There were 57 isolates selected for evaluation, 20 MRSA, 20 vancomycin-intermediate S. aureus (VISA), 7 daptomycin-nonsusceptible S. aureus (DNSSA), 6 linezolid-nonsusceptible S. aureus (LNSSA), and 4 heteroresistant VISA (hVISA) isolates. MICs and minimal bactericidal concentrations were determined using the broth microdilution method according to CLSI guidelines. All of the isolates were analyzed by pulsed-field gel electrophoresis. The staphylococcal cassette chromosome mec element (SCCmec) types were determined by a multiplex PCR. Population analysis profiles (PAPs) were performed to determine heteroresistance for all of the isolates using plates made by adding various amounts of ceftaroline to brain heart infusion agar. The frequencies of resistant subpopulations were 1 in 10 4 to 10 5 organisms. We determined that 12 of the 57 (21%) isolates tested were ceftaroline-heteroresistant S. aureus (CHSA). CHSA occurred among strains with reduced susceptibilities to vancomycin, daptomycin, and linezolid but occurred in none of the USA-300 isolates tested. Evaluation of the heteroresistant strains demonstrated that the phenotype was unstable. Further studies are needed to determine whether CHSA has a role in clinical failures and to determine the implications of our study findings.