Accelerating the clinical introduction of novel antibiotic combinations effective against Gram-negative pathogens

About the Project

Strathclyde Minor Groove Binders (S-MGB) lead compounds have in vivo activity (MIC = 0.2 µg/mL) against Gram-positive bacteria.^[1-5] In 2015 our commercial partner, MGB Biopharma, completed the successful Phase I Clinical Trial (NCT02518607) of our lead candidate MGB-BP-3 for the treatment of Clostridium difficile infections. MGB-BP-3 is taken up selectively by bacterial cells and interacts with bacterial DNA. Its mode of action is consistent with the arrest of transcription of a number of essential genes. Thus, the multi-target nature of binding of MGB-BP-3 may indicate why we have never seen mutation to resistance for this compound. Several bacterial resistance mechanisms would thus have to be developed at once for a new MGB drug to become ineffective.

In pilot studies, we have now demonstrated that co-administration with the efflux pump inhibitor, and cell membrane permeabiliser, PaβN significantly enhances the activity of otherwise non-Gram-negative active S-MGBs. This has led to the hypothesis that achieving insufficient intracellular accumulation of S-MGBs is the principal reason for their lack of antimicrobial activity towards Gram-negative organisms. Further work has already allowed the exploration of this hypothesis by extensively investigating the synergy between ceftazidime and MGB-BP-3 against a multi drug resistant (MDR) clinical isolate of K. pneumoniae. Thus, this in vitro experiment demonstrates the potential of MGB-BP-3 to ‘repurpose’ ceftazidime for clinical use.

Taken together, the results from the EPI potentiation experiments and the antibiotic synergy experiments, afforded by the Seed Award, demonstrate that MGB-BP-3 has the potential to be developed into a Gram-negative active combination therapy once an optimised combination is identified.

This project consists of assessing S-MGBs in combination with an extensive array of potential synergy partners. Antibiotics with several varieties of mechanisms of action will be investigated, noting the likelihood of success in cell wall or cell membrane modulators, such as the Beta-lactams or aminoglycosides, respectively. Success has already been observed with the efflux pump inhibitor PAβN, so we will investigate entities such as 1-(1-naphthylmethyl)piperazine, MC-278,537, alkoxy-quinolines. However, PAβN has been observed to have membrane permeabilising properties, thus generic cell permebilisers such as polymyxin B nonapeptide will also be investigated. AMPs have also seen extensive investigation in combination approaches, again due to their membrane permeabilising properties, thus several types of these will be investigated, such as hLF1-11, a cationic fragment of human lactoferricin, or Omiganan, derived from bovine indolicidin, both of which are progressing through clinical trials (NCT00509938 and NCT00231153, respectively).

Combinations will be investigated initially through standard checkerboard assays, by determining ∑FIC values, proceeding to more detailed investigations, such as time-kill, and growth kinetics, where warranted. Significantly, we have the capacity to use highly fluorescent S-MGBs in these synergy studies, which will allow the investigation of intracellular accumulation.

This project will seek to identify promising potential treatments for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, although I will also screen for activity against Gram-positive ESKAPE pathogens for completeness. Single compounds, or compound combinations, which show potential in the initial screen will undergo examination against a panel of MDR clinical isolates. Preliminary screens of clinical isolates will use Gram-negative pathogens within a collection of around 20 that have already been provided by NHS Lanarkshire. Active compounds/combinations identified in this preliminary screen will undergo further evaluation against clinical isolates to be collected during the course of this project. Although Gram-negative pathogens are the focus, Gram-positive pathogens will also be evaluated for completeness, including clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant enterococci (VRE).

Training Environment

Using advanced hit compounds identified from preliminary studies, in collaboration with national and international partners, the prospective student will carry out a comprehensive and systematic drug discovery campaign to identify new lead compounds and combinations for bacterial infections. This will involve routine and complex antimicrobial susceptibility testing, and also target engagement studies using biophysical techniques.

This project will suit a student with a background in microbiology or medicinal chemistry.

In addition to undertaking cutting edge research, students are also registered for the Postgraduate Certificate in Researcher Development (PGCert), which is a supplementary qualification that develops a student’s skills, networks and career prospects.

How To Apply

An upper second-class UK Honours degree or overseas equivalent in a relevant discipline is required. If English is not your first language, you must have an IELTS score of at least 6.5 with no component below 5.5

Interested candidates should email Dr Fraser Scott in the first instance.

Funding Notes

This project is suitable for self-funded candidates only. This may be through a personal scholarship that has already been secured or for an identified scholarship that a candidate would like to apply for with the supervisor.

References

1. 1 F. Giordani, F. J. Scott et al., J. Med. Chem., 2019, 62, 3021-3035.
   2. 2 F. J. Scott et al., Euro. J. Med. Chem., 2016, 116, 116–125.
   3. 3 H. Lerato, F. J. Scott et al. J. Antimicrob Chemother., 2017, 72, 3334–3341.
   4. 4 F. J. Scott et al., Eur J Med Chem., 2017, 18, 561-572.
   5. 5 F. J. Scott et al., Bioorg. Med. Chem. Lett., 2016, 26, 3478-86