Beta-lactams are a large family of antibiotics including amongst others penicillins, cephalosporins and carbapenems. They represent 65% of the antibiotics sold throughout the world and a large part of research efforts in the past decades.
They target bacterial Penicillin-Binding Proteins (PBP) and their efficacy is increasingly challenged by Gram-negative bacteria due to the rapid dissemination of beta-lactamase resistance genes responsible for their fast in situ degradation.
Discovered in the late 90’s, the Diazabicyclooctanes or DBOs are non-natural mimics of the beta-lactams. Initially developed as beta-lactamase inhibitors (Avibactam), their ability to inhibit PBPs, especially PBP2, has led to the development of hybrid inhibitors of beta-lactamases and PBP2, again to be used in combination with beta-lactams.
At MUTABILIS, we are developing a novel class of Diazabicyclooctanes.
By inhibiting not only PBP2 but also PBP1 and 3, these compounds called DABOCINS are direct-acting bactericidal antibacterials like carbapenems or cephalosporins. But unlike the latter, Dabocins show exceptional stability to class A, B, C, D beta-lactamases, and are thus still active against highly problematic carbapenem-resistant isolates.
EBL-1463 is a potential first-in-class representative of the Dabocin family, entering preclinical development against Enterobacterales. This compound inhibits several PBPs like beta-lactams, but is highly stable to all the beta-lactamases so far tested, thus setting the base for a new start with the most successful antibiotic class. EBL-1463 shows a very promising in vivo efficacy against Carbapenem Resistant Enterobacteriaceae (CRE) including NDM-producing isolates. This program is supported by IMI-ENABLE.
This Lead-to-Candidate program aims at identifying a next generation Dabocin covering both Enterobacterales and non-fermenters such as P. aeruginosa and A. baumannii.
Mutabilis develops a novel oral treatment to tackle cUTI/AP in the context of increasing beta-lactam / fluoroquinolone co-resistance. A third generation Cephalosporin is combined with EBL-2253, a potent DBO-based prodrug inhibitor of class A ESBLs, KPC and OXA-48. This combination is expected to reduce the use of carbapenems, and to prevent or reduce in-hospital stay. The program is in preclinical stage and is supported by IMI-ENABLE.