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ABSTRACTThe in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC90, 0.5 to 1 μg/ml), streptococci (all MICs, ≤0.12 μg/ml), and VanB-type enterococci (all MICs, ≤2 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of telavancin.

Potent in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA) has been difficult to achieve with previously reported DNA binding antibacterials. Herein, we describe an efficient access to a focused library of new analogues yielding compounds with improved activity in a mouse peritonitis model. The most potent molecules (14 and 19) exhibit efficacy against MRSA at ED50 values of ~1 and ~5 mg/kg, respectively, and display excellent in vitro activity against vancomycin-resistant S. aureus.

ABSTRACTGSQ1530 is a compound derived from a newly identified class of antibiotics referred to as heteroaromatic polycyclic (HARP) antibiotics. The aim of this study was to assess the in vitro antimicrobial activity of GSQ1530. By using an NCCLS broth microdilution assay, the activities of GSQ1530 and other antibiotics were coevaluated against 215 clinical isolates. The MICs at which 90% of isolates are inhibited (MIC90s) of GSQ1530 for methicillin-susceptible Staphylococcus aureusand methicillin-resistant S. aureus(MRSA) were 2 and 4 μg/ml, respectively. The MIC90s of GSQ1530 for the streptococci tested were 2 μg/ml or less, regardless of their susceptibilities to other antibiotics. The MIC90of GSQ1530 for the enterococci tested (including vancomycin-resistant enterococci) was 4 μg/ml. No cross-resistance was found between GSQ1530 and other known antibiotics. In a separate assay, GSQ1530 demonstrated excellent activity against vancomycin-intermediate-susceptible staphylococci (MIC90, 1 μg/ml). The minimal bactericidal concentration test was conducted with 73 clinical isolates; GSQ1530 was cidal against streptococci and staphylococci but static against enterococci. An in vitro killing kinetic study revealed a time-dependent profile, with at least a 3-log reduction of bacterial growth within 6 h after exposure to four times the MICs of GSQ1530 for both S. aureusand Streptococcus pneumoniae. The checkerboard study showed that GSQ1530 had a synergistic interaction with rifampin against MRSA. The test medium was found to have little effect on in vitro antimicrobial potency. The MICs of GSQ1530 for gram-positive cocci were 4- to 32-fold higher in the presence of serum proteins. GSQ1530 has high levels of plasma protein binding (91 and 89% for rat and human plasma, respectively). These preliminary results demonstrate that GSQ1530, a representative compound of our novel HARP antibiotics, has broad-spectrum activity against gram-positive bacteria. This novel class of antibacterial compounds is profiled in vivo to assess the therapeutic potential in humans. Ongoing in vivo studies will assess whether this class of molecules has promising in vivo efficacy and safety profiles.

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<it>Objectives</it>: BB-83698 is a peptide deformylase inhibitor currently in clinical trials in Europe. The purpose of this study was to provide additional susceptibility data from clinical isolates, including drug-resistant strains. <it>Methods</it>: The <it>in vitro</it> activities of BB-83698 and comparators were determined against 281 streptococci, 154 <it>Staphylococcus aureus,</it> 110 <it>Haemophilus influenzae</it> and 50 <it>Moraxella catarrhalis</it> strains selected for their resistance phenotypes. Broth microdilution MICs and MBCs were determined according to NCCLS guidelines. <it>Results</it>: The MIC<inf>90</inf>s were 0.25–0.5 mg/L for <it>S. pneumoniae</it>, including penicillin-, erythromycin-, levofloxacin- and multidrug-resistant strains. The MIC<inf>90</inf>s for <it>Streptococcus pyogenes</it> and <it>Streptococcus agalactiae</it> were 0.12 mg/L and for viridans streptococci, the MIC<inf>90</inf> was 0.5 mg/L. Against <it>S. aureus</it>, including oxacillin- and levofloxacin-resistant strains, and vancomycin-intermediate strains, the MIC<inf>90</inf> was 8 mg/L. Against &bgr;-lactamase-negative and -positive <it>H. influenzae</it>, the MIC<inf>90</inf>s were 32 and 64 mg/L, respectively, and against both &bgr;-lactamase-negative and -positive <it>M. catarrhalis</it> the MIC<inf>90</inf> was 0.12 mg/L. In MBC studies, the ratio of MBC/MIC was 1:1 or 2:1 against 31% of <it>S. pneumoniae,</it> 33% of <it>S. aureus,</it> 63% of <it>H. influenzae</it> and 9% of <it>M. catarrhalis</it>. <it>Conclusions</it>: Although BB-83698 has reduced <it>in vitro</it> activity against <it>H. influenzae</it>, it is a potent antimicrobial with excellent activity against streptococci and <it>Moraxella</it>.

<it>Objective</it>: BB-81384, a novel peptide deformylase (PDF) inhibitor, was characterized in terms of enzyme inhibition profile, antibacterial activity, rodent pharmacokinetics and oral efficacy in murine infection models. <it>Methods</it>: MICs were determined by standard NCCLS broth microdilution. Selectivity of metalloenzyme inhibition was determined with a limited panel of enzymes via standard biochemical assays. Profiling of the pharmacokinetics and select tissue disposition in mice was determined and compared with that of the macrolide, azithromycin. <it>In vivo</it> murine efficacy studies using <it>Streptococcus pneumoniae</it> were conducted using a peritonitis model, as well as lung and thigh burden models of infection. <it>Results</it>: BB-81384 selectively inhibited PDF with an IC<inf>50</inf> ∼10 nM and with MICs < 0.5 mg/L against most <it>S. pneumoniae</it> pathogens. Pharmacokinetic analysis revealed good oral bioavailability and moderate clearance and volume of distribution. BB-81384 partitioning to lung tissue was similar in terms of magnitude and kinetics to that of the plasma compartment. Single-administration oral efficacy in a mouse peritonitis model was evident with an ED<inf>50</inf> of 30 mg/kg. BB-81384 reduced the bacterial load by ∼5 and 3 log units in organ-burden models of lung and thigh infection, respectively. <it>Conclusion</it>: BB-81384, a novel PDF inhibitor with good activity against <it>S. pneumoniae</it> <it>in vitro</it>, was the first compound of this class to be profiled for oral pharmacokinetics and tissue disposition and to demonstrate oral anti-pneumococcal efficacy in mice.