4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.

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 [ , 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 (ED 50 ) 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 ED 50 to reduce the bacterial lung burden by >4 log 10 in 50% of treated animals was 23.3 mg/kg for LBM415, whereas moxifloxacin showed an ED 50 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.With the emergence of pathogens resistant to current clinically used antibiotics, the need for new therapies has become of paramount importance. A novel class of antibacterial agents to emerge from research in this field is the peptide deformylase (PDF) inhibitors. PDF is a highly conserved metalloenzyme which deformylates the initial N-formyl methionine of newly synthesized bacterial polypeptides. This is an important step in bacterial protein synthesis, thus making it an attractive antibacterial target. The role of PDF and its attractiveness as an antibacterial target have previously been reviewed (10,11,15,16).LBM415 is one of the first compounds of the PDF inhibitor class to advance to clinical trials for the oral (p.o.) and parenteral treatment of respiratory tract and skin and skin structure infections caused by susceptible gram-positive and -negative organisms. LBM415 has been evaluated previously in vitro in comparison with other antibiotics and demonstrated potent activity against clinical strains of staphylococci, streptococci, enterococci, Moraxella catarrhalis, Legionella pneumophila, and Haemophilus influenzae (2,5,6,9,13,14). There was no difference in activity against strains classified as being susceptible or resistant to other classes of antibiotics. LBM415 also displayed activity against a collection of other gram-positive species, including Aerococcus spp., Bacillus spp., Corynebacterium ...