Beta-lactams are a large family of antibiotics that include, amongst others, penicillins, cephalosporins and carbapenems. They target bacterial Penicillin-Binding Proteins (PBP). They represent 65% of the antibiotics sold throughout the world and a large part of research efforts in the past decades. Their efficacy is increasingly challenged in Gram-negative bacteria by 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 highly promising non-natural mimics of the beta-lactams.
Considering their remarkable properties with regard to beta-lactamase resistance, and our extensive experience of DBO chemistry, Mutabilis focuses on 2 programs:
– DABOCINS : New DBO inhibitors of PBPs, stable to all beta-lactamases
– ORAL CEPHALOSPORIN/BETA-LACTAMASE INHIBITOR combination: novel inhibitor prodrugs of beta-lactamases to protect third generation oral cephalosporins.
We have also developed at Mutabilis a series of potent antibacterial potentiators which weaken bacterial cell membrane and virulence by interfering with normal LPS synthesis. They are inhibitors of GmhA.
Dabocins are Diazabicyclooctane (DBO) derivatives that specifically target PBP, as beta-lactams do. These new antibiotics have a key advantage over beta-lactams: they are stable to all beta-lactamases. Dabocins are active against gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE) and potentially P. aeruginosa. They are bactericidal with a very low frequency of resistance, and are active in vivo against CREs. The targeted profile is intravenous treatment of hospital infections caused by gram-negative bacteria. This program is in Lead Optimization stage
ORAL CEPHALOSPORIN/BETA-LACTAMASE INHIBITOR COMBINATION
Mutabilis develops a novel oral treatment to tackle cUTI/AP in the context of increasing beta-lactam / fluoroquinolone co-resistance: the combination of MUT485 with an oral Cephalosporin. MUT485 is the prodrug of MUT350, a potent DBO-based 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. This program is in preclinical stage.
Since its inception, MUTABILIS has been working on new approaches to fight against invasive bacterial infections different from traditional antibiotics: the antivirulents. While antibiotics target genes essential for the survival of bacteria, antivirulent compounds target non-essential genes involved in bacterial virulence, and/or resistance to host immunity. By weakening the cell membrane of Gram-negative bacteria, these compounds can act as antibacterial potentiators.
These explorations have led us to the discovery of highly potent GmhA inhibitors able to block bacterial LPS heptosylation, thus weakening the first barrier opposed by Gram-negative bacteria to antibacterials. These compounds are active against diverse multiresistant species of clinical isolates, and potentiate the activity of Erythromycin.