Activity of Debio1452, a FabI Inhibitor with Potent Activity against Staphylococcus aureus and Coagulase-Negative Staphylococcus spp., Including Multidrug-Resistant Strains

Abstract

Staphylococcus aureus and coagulase-negative staphylococci (CoNS) are responsible for a wide variety of human infections. The investigational antibacterial Debio1450 (previously AFN-1720), a prodrug of Debio1452 (previously AFN-1252), specifically targets staphylococci without significant activity against other Gram-positive or Gram-negative species. Debio1452 inhibits FabI, an enzyme critical to fatty acid biosynthesis in staphylococci. The activity of Debio1452 against CoNS, methicillin-susceptible S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA), including significant clones, was determined. A globally diverse collection of 574 patient isolates from 35 countries was tested that included CoNS (6 species, 103 strains), MSSA (154 strains), MRSA (163 strains), and molecularly characterized strains (including spa-typed MRSA clones; 154 strains). The isolates were tested for susceptibility by CLSI broth microdilution methods against Debio1452 and 10 comparators. The susceptibility rates for the comparators were determined using CLSI and EUCAST breakpoint criteria. All S. aureus and CoNS strains were inhibited by Debio1452 concentrations of <0.12 and <0.5 g/ml, respectively. The MIC 50 s for MSSA, MRSA, and molecularly characterized MRSA strains were 0.004 g/ml, and the MIC 90 s ranged from 0.008 to 0.03 g/ml. The MICs were higher for the CoNS isolates (MIC 50/90 , 0.015/0.12 g/ml). Among S. aureus strains, resistance was common for erythromycin (61.6%), levofloxacin (49.0%), clindamycin (27.6%), tetracycline (15.7%), and trimethoprim-sulfamethoxazole (7.0%). Debio1452 demonstrated potent activity against MSSA, MRSA, and CoNS. Debio1452 showed significantly greater activity overall (MIC 50 , 0.004 g/ml) than the other agents tested against these staphylococcal species, which included dominant MRSA clones and strains resistant to currently utilized antimicrobial agents. Inhibitors of the fatty acid biosynthetic pathway have emerged as part of a potential approach to developing antibacterial agents (1-6). Among those inhibitors, Debio1452 (previously designated AFN-1252) was characterized for its specific activity against FabI, an essential enzyme involved in the final step of the elongation cycle of bacterial fatty acid biosynthesis (7,8). Debio1452 is a novel FabI inhibitor that specifically targets Staphylococcus species (7)(8)(9)(10)(11). This compound has demonstrated a lack of activity against other species of bacteria, including streptococci, enterococci, Enterobacteriaceae, and nonfermentative Gram-negative species (9, 11).The narrow targeted spectrum (staphylococci) exhibited by Debio1452 provides the benefit of minimizing the effect on normal bacterial flora and hence the potential for reduced antibioticassociated adverse events, such as overgrowth of resistant commensals, diarrhea, and candidiasis. Further, its unique mode of action lessens the likelihood that resistance development to Debio1452 would lead to cross-resistance with currently available antimicrobial agents. A phase 2a study has be...

Antibiotics in the clinical pipeline at the end of 2015

“…236 Affinium licensed the program in 2002 and conducted further structure optimization leading to AFN-1252 (39). 232,[238][239][240][241][242][243][244][245] In February 2014, Debiopharm Group (Lausanne, Switzerland) acquired Affinium's antibiotic assets, including both 39 and a prodrug of AFN-1252, Debio-1450 (AFN-1720). 246 The prodrug, Debio-1450, was assessed in two phase-I studies (NCT02162199 and NCT02214433), with a third (NCT02595203) scheduled for completion in December 2015.…”

A Pathogen-Selective Antibiotic Minimizes Disturbance to the Microbiome

“…Debio 1452 is also highly selective for staphylococcal FabI compared to the essential FabIs expressed in other bacteria, due to a specific drug interaction with an active-site methionine that is unique to staphylococcal FabI (12,23). Consequently, Debio 1452 has potent activity against Staphylococcus aureus and other staphylococcal spp., including multidrug-resistant isolates, but does not inhibit the growth of bacteria of many other Gram-positive or Gram-negative genera (24). These considerations suggest that Debio 1452 therapy may have minimal impact on the gut microbiome.…”

Initial Broth Microdilution Quality Control Guidelines for Debio 1452, a FabI Inhibitor Antimicrobial Agent

“…Such new agents should have enhanced activity and potency against these multidrug-resistant staphylococci and possess novel targets, where possible. Debio 1452 is such a new agent directed against the FabI target found in staphylococci (MIC 90 , 0.008 to 0.12 g/ ml) (1). These MIC quality assurance guidelines (Fig.…”