Activity of LBM415 Compared to Those of 11 Other Agents against Haemophilus Species

Abstract

When tested against 254 Haemophilus influenzae strains, LBM415, a peptide deformylase inhibitor, gave MIC 50 and MIC 90 values of 2.0 g/ml and 8.0 g/ml, respectively. The MICs were independent of ␤-lactam or quinolone susceptibility and the presence or absence of macrolide efflux or ribosomal protein mutations. The MICs of LBM415 against 23 H. parainfluenzae strains were similar to those against H. influenzae. In contrast, erythromycin, azithromycin, and clarithromycin gave unimodal MIC distributions, and apart from ␤-lactamase-negative, ampicillin-resistant strains, all strains were susceptible to the ␤-lactams tested. Apart from selected quinolone-resistant strains, all strains were susceptible to ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin. Resistance to trimethoprim-sulfamethoxazole was common. The potencies of all drugs against 23 H. parainfluenzae strains were similar to those against H. influenzae. Time-kill studies with 10 Haemophilus strains showed LBM415 to be bactericidal at 2؋ the MIC against 8 of 10 strains after 24 h. For comparison, the macrolides and ␤-lactams were bactericidal against 8 to 10 strains each at 2؋ the MIC after 24 h. Quinolones were bactericidal against all 10 strains tested at 2؋ the MIC after 24 h. Against six H. influenzae strains, postantibiotic effects for LBM415 lasted between 0.8 and 2.2 h. In multistep resistance selection studies, LBM415 produced resistant clones in 7 of the 10 strains tested, with MICs ranging from 4 to 64 g/ml. No mutations in deformylase (def) and formyltransferase (fmt) genes were detected in any of the LBM415-resistant mutants.Haemophilus influenzae is an important pathogen responsible for community-acquired respiratory tract infections in children and adults, including pneumonia, acute exacerbations of chronic bronchitis, sinusitis, and otitis media (9, 23). In countries such as the United States, where the H. influenzae type b vaccine is widely used, type b has been replaced by untypeable H. influenzae strains. Haemophilus parainfluenzae strains may also play a role in the pathogenesis of acute exacerbations of chronic bronchitis (S. Sethi, personal communication).Antimicrobials used for the empirical treatment of Haemophilus infections include ␤-lactams, macrolides, and (in adults) fluoroquinolones. The major resistance mechanism in H. influenzae in the United States and Europe is the production of ␤-lactamase (encoded by bla TEM-1 and, rarely, bla ROB-1 ), which is present in over 41% of H. influenzae strains in the United States (17,24,27,30). Although less common, resistance to ␤-lactams in the absence of ␤-lactamase production (␤-lactamase-negative ampicillin resistance [BLNAR]) is caused by alterations (mutations) in penicillin-binding protein 3 (8, 31). Strains producing ␤-lactamases remain susceptible to amoxicillin-clavulanate; however, clavulanate is not active against BLNAR strains. In addition, very rare H. influenzae strains producing ␤-lactamase have been found to be resistant to amoxicillin-clavulanate (8...

Comparative Analysis of the Antibacterial Activity of a Novel Peptide Deformylase Inhibitor, GSK1322322

“…Moxifloxacin, on the other hand, shows a much faster killing effect than GSK1322322 against both organisms. These results are similar to those observed with the PDF inhibitor LBM415 in H. influenzae (31) and S. pneumoniae (32). However, GSK1322322 seems to demonstrate more of a bactericidal effect against S. aureus than previously reported for LBM415 (22,33) and is clearly differentiated from linezolid.…”

Efflux-Mediated Drug Resistance in Bacteria

“…[319, 320] Overproduction of AcrAB (due to AcrR mutations) and alterations in penicillin-binding protein 3 were observed in β-lactamase-negative, high-level ampicillin-resistant H. influenzae of diverse geographical sources. [321] Single cysteine mutations were constructed in AcrB in positions identified as important for substrate recognition in order to investigate the accessibility of the cysteine to the hydrophilic thiol-reactive fluorophore fluorescein-5-maleimide and the results suggest that substrates induce conformational changes in AcrB.…”

Advances in MRSA drug discovery: where are we and where do we need to be?

“…Previously, potent peptide deformylase inhibitors, BB-83698 and LBM415 (NVP PDF-713) were developed by British Biotech Pharmaceuticals (Oxford, UK) in collaboration with Genesoft Pharmaceuticals (South San Francisco, CA) and Novartis, respectively. Both molecules were evaluated in phase I clinical studies, but are no longer being developed for the treatment of community-associated respiratory tract infections and various uncomplicated and complicated Gram-positive infections [92, 93]. …”