Inhibition of metallo-ß-lactamases (MBLs) to fight the bacterial resistance to ß-lactam antibiotics – ANTIMBL

Bacterial resistance to antibiotics is a growing threat to public health and endangers the effective treatment of infections. In Europe and other industrialized countries, the highest proportion of resistant bacteria is found in healthcare facilities. Today, about 70% of bacteria that cause nosocomial infections are resistant to at least one of the drugs most commonly used to treat them. About 25,000 patients die every year in E.U. because of bacterial resistance. It adds about 1.5 billion € of healthcare-associated costs. Although the situation is alarming, pharmaceutical companies have for a long time lost interest in the discovery and development of novel antibiotics. Public research is thus crucial in the field of antimicrobial therapy to identify novel and innovative approaches.
In Gram-negative bacteria, the major mechanism of resistance to ß-lactam antibiotics (penicillins, cephalosporins, carbapenems), the most widely used antimicrobials, is the production of one or several ß-lactamase(s). One major approach to overcome this issue consists of combination therapy in which a ß-lactam drug is given along with a ß-lactamase inhibitor, which protects the former from inactivation. Several ß-lactamase inhibitors (clavulanic acid,…) are currently marketed, but they only target serine-ß-lactamases (SBL) and are not active on metallo-ß-lactamases (MBL). There is still much work to accomplish to find clinically useful inhibitors of the increasingly important Ambler class B MBL. MBLs contain one or two Zn cation(s) in their active site, and are structurally and mechanistically unrelated to SBLs. MBLs are classified into three subclasses, B1, B2, and B3 on the basis of structural features. Subclass B1 includes most of the acquired enzymes, encoded by mobile genetic elements. Clinically-relevant B1 MBLs, including IMP-, VIM- and NDM-type enzymes, are currently disseminating in important opportunistic Gram-negative pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumanii. Compared to most SBLs, MBLs exhibit an exceedingly broad substrate profile as they constantly inactivate carbapenems, antibiotics of last resort at the hospital. Moreover, MBL-producing clinical isolates very often show multidrug- and even pandrug-resistance phenotypes, thus representing an increasingly important medical threat that could be successfully addressed by the development of potent, safe and selective MBL inhibitors.

In this project, we propose to develop a new and recently identified class of MBL inhibitors, which possess an original Zn-coordinating group. The synthesis of a first generation of compounds incorporating this group has been achieved and some inhibitors already showed efficient inhibition of selected enzymes of the three sub-classes, thus supporting the rationale that broad-spectrum inhibition of MBLs could be achieved.
Our objective is to optimize, on the basis of our current knowledge, this completely novel and still unexploited series of MBL inhibitors toward lead compounds that could potentially be amenable to clinical development. The iterative optimization of the inhibitors will be supported by an innovative combination of in silico methods using quantum chemistry and polarizable molecular dynamics approaches, which are the most reliable methods for metallo-enzymes, and X-ray crystallography. The inhibition of clinically-relevant B1 enzymes is the main target, but we will also explore the feasibility of optimizing inhibitors with a broader spectrum of activity. This might be important considering the recent emergence of several acquired subclass B3 enzymes in relevant opportunistic pathogens (AIM-1, SMB-1). If successful, this project is expected to have an important impact in the field of antimicrobial research, as it could represent a viable starting point to develop therapies to treat infections caused by MBL-producing MDR/XDR Gram-negative pathogens, which represent an extremely urgent clinical need.