Title: SAMRC Award - University of Oxford
Funder: Medical Research Council

Abstract: Recent surveillance data reveals that the incidence of serious gram-negative infections is increasing in Sub- Saharan Africa1. Unfortunately, treatment options for these Gram-negative infections using β-lactams, which remain the most important class of antibiotics, is significantly compromised by the presence of serine- and/or zinc metallo-β- lactamases in clinical strains of E. coli, K. pneumoniae, E. cloacae, A. baumannii and P. aeruginosa2,3. Worldwide, >1800 β-lactamases have been identified that can reduce or ablate the efficacy of β-lactam antibiotics via lactam hydrolysis3. There is a clear need for more treatment options to address this health threat, both in South Africa and globally. Most pressing is a clinically useful agent capable of treating infections caused by a Gram-negative bacteria containing a New Delhi metallo-β -lactamase (NDM-1), imipenem-style metallo-β -lactamase (IMP) or Verona integron-encoded metallo- β-lactamase (VIM). The monobactam Aztreonam is the only β-lactam which is relatively stable to metallo-β- lactamase2; however, it is labile to serine β-lactamases. Hence new monobactams that are more stable to serine β- lactamases will aid in the fight against resistant gram-negative bacteria, especially those classified as carbapenemaseresistant Enterobacteriaceae (CRE). Specifically, this project will focus on building capacity and collaboration between South Africa and the UK within the context of research addressing two main needs in the fight against antimicrobial resistance (AMR): 1) Optimization of the recently discovered novel cyclic boronate dual serine- and metallo-β-lactamase inhibitors that can be used singly or in combination with existing antibiotics to treat serious Gram-negative infections 2) Identification of novel monocyclic β-lactam antibiotics for the treatment of serious Gram-negative infections One aspect of the work will focus on H3D profiling the drug metabolism and pharmacokinetic (DMPK) properties of the novel cyclic boronates discovered in the labs of Schofield and Fishwick5. DMPK study results will be jointly discussed among the collaborators to decide if the current cyclic boronates can be progressed to an animal efficacy study, or if further optimization of the series needs to be done. This effort will provide an opportunity for researchers in the collaborating teams to learn about the compound characteristics necessary for a successful Gram-negative infection animal study and to determine optimal dosing regimens for an eventual combination therapy. At the same time, work will begin in order to build a strong knowledge base on Penicillin Binding Protein (PBP) structure-activity relationships (SAR) and how that SAR and available PBP X-ray structures can be used in conjunction with the recent high quality hits obtained from X-ray fragment screening against PBP-3 and VIM-2 to design improved novel monobactam PBP inhibitors resistant to β-lactamases. Synthesis of the newly designed monobactams will be carried out and biochemical and microbiological profiling performed against a panel of PBPs and gram-negative bacteria to test the validity of the design ideas.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION