ANTIBIOTHERAPY

Tetiere-bacterie-RD

The rise in bacterial resistance to antibiotics today constitutes a public health challenge

The lack of R&D investment in the sector for decades has led to pipeline attrition, and the widespread use of available antibiotics has fostered the emergence of resistant bacteria, against which we have treatments that are increasingly less effective.

When pathogens developed beta-lactamases (classes A, B, C and D) to hydrolyse and counter the action of beta-lactams, beta-lactamase inhibitors (class A) were developed to be used in combination with beta-lactams. Several studies have been carried out to identify new series of PBP and beta-lactamase inhibitors, though few have been successful. The most prominent discovery is certainly the DBO series discovered by Aventis in the late 90s.

Gram-negative bacteria, due to their double membrane and efflux pumps, are the bacteria against which it is most difficult to develop antibiotics. These bacteria are those that today show the most worrying resistance; some of which resist all front-line antibiotic treatments.

Beta-lactams are a large family of antibiotics that include, amongst others, penicillins, cephalosporins and carbapenems, and target PBPs (penicillin-binding proteins). It represents 65% of the antibiotics sold throughout the world and a large part of research efforts in the past decades.

Research at the heart of MUTABILIS:

DABOCINS

Dabocins are DBO derivatives that specifically target PBP, like b-lactams. These new antibiotics have an essential advantage over b-lactams: they are impervious to the resistance induced by b-lactamases. Dabocins are active against gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE) and potentially P. aeruginosa. These compounds are bactericides, present very a low frequency of resistance, and are active in vivo. The targeted profile is intravenous treatment of hospital infections caused by gram-negative bacteria.

INHIBITORS OF ORAL b-LACTAMASES

These b-lactamase inhibitors, also DBO derivatives, present excellent oral bioavailability compared to those previous. In combination with oral cephalosporin, they mainly target the treatment of urinary infections caused by the Enterobacteriaceae producing ESBLs and KPC and OXA-48 type carbapenemases.

Tetiere bandeau Bacterie Gram neg Mutabilis2

MUTABILIS targets virus-host interaction and develops a new generation of antiretroviral drugs

New antiretroviral generation

To address this problem, MUTABILIS is developing a new generation of original and innovative antiretrovirals drugs, based on a new mode of therapeutic action. Instead of targeting the catalytic activity of viral enzymes, like most drugs, MUTABILIS targets virus-host interaction that is essential for viral replication. Drugs operating through this new mode of action offer key advantages: complementarity with all other existing drugs and a lack of sensitivity to cross-resistance mechanisms.

Host-virus interaction

The host-virus interaction is an emerging field in the pathogenesis of viral diseases. The scientific Director at MUTABILIS, R. Benarous, has contributed to the discovery of LEDGF as a cellular co-factor of HIV integrase essential in the integration and full replication of the virus. LEDGF, by binding to integrase, allows the integration of HIV in the transcriptionally active regions of chromatin. Early 2010, the MUTABILIS program began with the searching for drugs targeting the interaction between integrase and LEDGF. This program led to the discovery of new powerful and promising antiviral agents, one of them is currently in pre-clinical phase.

Mutabilis drug candidate

This drug candidate and its backups are original allosteric inhibitors of integrase-LEDGF interaction (INLAIs) that were co-crystallized with the catalytic domain of the integrase in the LEDGF binding site. They present a potent antiretroviral activity in the nanomolar range, are active against all tested HIV-1 isolates, including isolates from various clades, and kept their full activity against resistant viruses to current drugs. MUTABILIS Researchers (Le Rouzic et al. 2012)¹ and other teams² have recently shown that these INLAIs have a dual mode of action: first they inhibit viral integration and then they disturb, in the post-integration phase, the production of infectious viral particles. The antiretroviral activity of INLAIs at post-integration stage is by far the most important. This dual mode of action of INLAIs acting at two different stages of the replication cycle of HIV, is unique and unprecedented with other classes of antiretroviral agents. This could give a significant advantage to this new family of compounds from a therapeutic point of view. The lack of antagonism between INLAIs and INSTIs and other families of drugs currently on the market is an asset that enhances their potential as future antiretroviral drug.

Microscope
¹Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Le Rouzic E, Bonnard D, Chasset S, Bruneau JM, Chevreuil F, Le Strat F, Nguyen J, Beauvoir R, Amadori C, Brias J, Vomscheid S, Eiler S, Lévy N, Delelis O, Deprez E, Saïb A, Zamborlini A, Emiliani S, Ruff M, Ledoussal B, Moreau F, Benarous R. Retrovirology. 2013 Nov 21;10:144. doi: 10.1186/1742-4690-10-144.
²Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Jurado KA, Wang H, Slaughter A, Feng L, Kessl JJ, Koh Y, Wang W, Ballandras-Colas A, Patel PA, Fuchs JR, Kvaratskhelia M, Engelman A. Proc Natl Acad Sci U S A. 2013 May 21;110(21):8690-5. doi: 10.1073/pnas.1300703110. Epub 2013 Apr 22.