Developing Strathclyde minor groove binders as Novel Gram-negative active drugs

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Urgent action is required to develop novel antimicrobials to treat multidrug resistant bacterial infections. Without this, we risk slipping into a "post-antibiotic era" where a cut or simple operation is a life-threatening event, such as they were before the discovery of penicillin. Of particular concern is the lack of novel compounds for the treatment of Gram-negative bacteria, which are inherently more challenging due to the difficulty that antibiotics have in penetrating their cell envelope. Furthermore, the inherent ability of Gram-negative bacteria to induce efflux pumps that actively remove the antibiotic from the cell is another obstacle. These difficulties conspire to make Gram-negative bacteria a fundamentally challenging arena for antibacterial drug discovery.New antibiotics are needed now, yet it is well-established that at least 7-10 years are required to develop a drug. One way to mitigate this delay is to take advantage of work in progress, hence the significance of this research: one compound from our drug discovery platform, MGB-BP-3, has entered Phase IIa clinical trials in Q1 2019 for treatment of Clostridium difficile infections.[5] This proposal seeks to reduce the threat of Gram-negative pathogens through the comprehensive investigation of strategies to adapt an exclusively Gram-positive active class of antibiotic, Strathclyde Minor Groove Binders (S-MGB), towards treatment of Gram-negative infections. Significantly, the Strathclyde Minor Groove Binder project is currently one of the Department of Pure and Applied Chemistry's and SIPBS's Impact Case Studies for REF2021; this project seeks to sustain the impact of this project for both Departments, ready for the next REF.There already exists a variety of strategies that have been successfully applied to current exclusively Gram-positive active drug classes, extending their use to Gram-negative infections. The most significant problem with these strategies is that they have been applied to antibiotic classes that have already seen extensive use in the clinic: resistance will quickly develop, rendering these efforts futile. The goal of this research proposal is to apply these established strategies to our novel class of antibiotic, S-MGBs, to impart activity against Gram-negative organisms. The project is thus of minimal risk as these strategies have already been demonstrated to be successful. Moreover, not only is there an absence of an established reservoir of resistance to MGBs, but we have been unable to raise resistant mutants against bacteria when challenged with serial passaging. Proposed is an ambitious and comprehensive strategy with which to achieve this goal. Specifically, it will: (i) fully investigate the synergistic combinations of S-MGBs with efflux pump inhibitors, antimicrobial peptides, cell permeabilising agents, and existing antibiotics; (ii) select the best synergy partners and covalently tether them to MGBs yielding novel MGB-conjugates; however, we propose to go beyond simple conjugation by (iii) developing more drug-like S-MGB-hybrids, which contain the smallest set of structural features necessary for activity. Significantly, we will have access to the expertise and facilities at Public Health England for the duration of this project.Ultimately, compounds of significant activity will enter into our development pipeline with our industry partner MGB Biopharma.