Principal Investigator (PI)
The Foundation is providing £177,625 in support.
Jurgen Brem - Mariska de Munnik
Determination of anti Mtb activity in vitro and in vivo. Oxford University does not have the capacity required for this work, therefore a collaboration with GSK TC is essential for the project.
- Supply of compounds for testing in assays and structural evaluation (Note initial work will focus on compounds already available, with focused medicinal chemistry being the subject of a new funding application.)
- Expertise in mechanistic chemistry (including modeling) to be used in inhibitor design possibly coupled to modeling
- Assistance in project management including via frequent (Skype / phone) meetings
- Expertise in identifying routes to pre-clinical and clinical candidates
- A desire to work together to secure future large-scale funding to develop -lactam / analogous compounds to be used for Mtb treatment
- The ability to work collaboratively with Oxford to rapidly follow up breakthrough results on new types of inhibitor.
β-Lactams, including penicillins, cephalosporins and carbapenems, remain the most important antibiotics in use for treatment of Gram- and Gram+ bacteria, but their use is compromised by growing resistance, most importantly due to widespread β-lactamase dissemination. Mycobacteria tuberculosis (Mtb) has a higher mortality rate than any other infectious disease; however, β-lactams have traditionally not been effective in Mtb treatment. The paradigm that β-lactams are not useful for treatment of Mtb (including XDR Mtb) is based on the poor cell permeability/stability/oral use of ‘classical’ β-lactams (which poorly penetrate the cell-membrane) and the presence of a genetically encoded β-lactamase (BlaC) in Mtb. This paradigm is now being questioned [1-3], because: (i) Recent clinical trials shows that meropenem combined with amoxicillin–clavulanic acid has potential for treating Mtb; (ii) Carbapenems not only inhibit Mtb D,D-transpeptidases, but can also Mtb inhibit L,D-transpeptidases ; (iii) Clinically used cephalosporins in combination with clavulanic acid manifest synergistic effects in Mtb treatment; (iv) novel cephalosporins with C-2 carboxylate isosters have shown selective activity against non-replicating Mtb [3]. Thus, the timing is right for focused efforts to develop tailored β-lactams for Mtb treatment together BlaC inhibitors, the latter being the initial focus of our proposed work.
Such work will be enabled by contemporary availability of: (i) New types of transpeptidase / β-lactamase inhibitors, including new acylating agents, such as those based on avibactam and lactivicins [9], and ‘transition state analogues’ e.g. cyclic boronates that display remarkable potency against β-lactamases [5]; such compounds have potential as transpeptidase inhibitors with very different PK/PD properties compared to classical β-lactams; (ii) Extensive new structural and mechanistic information on β-lactam mode of action and resistance mechanisms has emerged since the classical β-lactams were developed; (iv) New synthetic methodologies enable access to complex densely functionalised rings systems (e.g. functionalized oxapenems) previously unviable due to ‘cost of goods’ issues; (v) Knowledge of (Mtb infected) human cell biology will enable more rational targeting of β-lactams to Mtb in human cells. The focus of this OpenLab project will be structural, screening, and mechanistic work (including involving new inhibitors types) that will enable future medicinal chemistry efforts to enable clinically useful BlaC resistant PBP inhibitors for oral Mtb treatment.