SMT19969 – a novel antibiotic for C. difficile : Clostridium difficile growth inhibition, spectrum of activity and resistance development

Abstract

Background: C.difficile infection (CDI) is now established as a major healthcare issue. However, therapy options are limited and recurrent disease remains a significant problem. SMT19969 is the lead compound from a novel class of narrow spectrum, GI restricted, antibiotics in preclinical development for the treatment of CDI. Methods: C. difficile minimum inhibitory concentrations (MIC) were determined by agar plate dilution on Wilkins Chalgren agar. MIC testing against gut flora bacteria was carried out using CSLI guidelines. Resistance development was evaluated by determining spontaneous mutation frequencies at 4x and 8x MIC and by serial passage over 14 days at sub-inhibitory (0.5 x MIC) drug concentrations. Results: SMT19969 showed potent C. difficile growth inhibition (MICs 0.06-0.25 mg/L; MIC90 = 0.125 mg/L) when tested against a panel of 82 clinical isolates comprised of 30 genotypically distinct strains, 31 isolates from ribotypes 027, 106 and 001 and 21 isolates with reduced susceptibility to metronidazole (MICs 4-8 mg/L). SMT19969 showed minimal growth inhibition against a panel of 100 isolates representing members of the gut flora. MIC90 values (mg/L) against each group were as follows: Bacteroides spp. >512; E. coli and other Proteobacteria > 512; Clostridium spp. other than C. difficile = 512; Lactobacillus spp. > 512; Eubacterium spp. = 512; Peptostreptococcus spp. = 128; Bifidobacterium spp. = 128.No drug resistant mutants were isolated. Spontaneous mutation frequencies using the C. difficile clinical isolates NCTC13366 and NCTC13307 were <3.17 x10-9 and <6.90 x10-9 respectively. No increase in SMT19969 MICs for C. difficile was seen despite 14 serial passages. Conclusions: The high activity and low rate of resistance development in C. difficile support the potential use of SMT19969 in the treatment of CDI. The extremely narrow spectrum of activity in gut bacteria testing offers the prospect of reduced risk of CDI recurrence due to flora inhibition