In vivo characterization of the peptide deformylase inhibitor LBM415 in murine infection models

Abstract

LBM415 is an antibacterial agent belonging to the peptide deformylase inhibitor class of compounds. It has previously been shown to demonstrate good activity in vitro against a range of pathogens. In this study, the in vivo efficacy of LBM415 was evaluated in various mouse infection models. We investigated activity against a systemic infection model caused by intraperitoneal inoculation of Staphylococcus aureus (methicillin [meticillin] susceptible [MSSA] and methicillin resistant [MRSA]) and Streptococcus pneumoniae (penicillin susceptible [PSSP] and multidrug resistant [MDRSP]), a thigh infection model caused by intramuscular injection of MRSA, and a lung infection produced by intranasal inoculation of PSSP. In the systemic MSSA and MRSA infections, LBM415 was equivalent to linezolid and vancomycin. In the systemic PSSP infection, LBM415 was equivalent to linezolid, whereas against systemic MDRSP infection, the LBM415 50% effective dose (ED50) was 4.8 mg/kg (dosed subcutaneously) and 36.6 mg/kg (dosed orally), compared to 13.2 mg/kg for telithromycin and >60 mg/kg for penicillin V and clarithromycin. In the MRSA thigh infection, LBM415 significantly reduced thigh bacterial levels compared to those of untreated mice, with levels similar to those after treatment with linezolid at the same dose levels. In the pneumonia model, the ED50 to reduce the bacterial lung burden by >4 log10 in 50% of treated animals was 23.3 mg/kg for LBM415, whereas moxifloxacin showed an ED50 of 14.3 mg/kg. In summary, LBM415 showed in vivo efficacy in sepsis and specific organ infection models irrespective of resistance to other antibiotics. Results suggest the potential of peptide deformylase inhibitors as a novel class of therapeutic agents against antibiotic-resistant pathogens.

FIG. 1.

Chemical structure of LBM415.

FIG. 2.

Efficacy of LBM415 and moxifloxacin against lung infection in mice by S. pneumoniae ATCC 6303. Oral treatments were given twice daily for 3 days, starting 16 h postinfection; bacterial counts per lung (log₁₀ CFU/lung) were plotted for each dose tested. *, P < 0.05 versus the control.

FIG. 3.

Efficacy of LBM415 and linezolid against S. aureus NB01021 (MRSA) in a mouse soft tissue infection. Treatment was administered three times daily for 2 days, and bacterial counts per thigh (log₁₀ CFU/thigh) were plotted for each dose tested. *, P < 0.05 versus the control.