New drugs to tackle AMR

GENERATOR FUND

Awarded: 2021

GW4 community leads
University of Bath: Maisem Laabei
University of Bristol: Seána Duggan, Jonathan M. Tyrrell
Cardiff University: Michaela Serpi (PI)
University of Exeter: Tobias Bergmiller, Remy Chait

Project overview

In this project, we will develop novel antimicrobial compounds to treat Gram-positive bacterial infections combining our expertise in drug discovery, organic synthesis, microbiology and molecular microbial ecology and evolution to enhance the ability of the agents to kill bacteria and interfere with biofilm formation.

Background

The global challenges research area which we would like to address is “Health, demographic change and wellbeing”. Specifically, we will build capacity to treat and manage bacterial infection.

AMR is expected to cause 10,000,000 deaths a year by 2050, with an associated $1 trillion global cost. Staphylococcus aureus is an organism of particular concern in the context of AMR, due to its ability to cause infection in, and adapt to, diverse host niches. Antimicrobial resistant strains of S. aureus (e.g. MRSA), cause a significant number of life-threatening hospital and community-acquired infections. It is estimated that up to 80% of S. aureus infections are caused by biofilms- that is a community of cells attached to a substrate (i.e. catheter) or each other, and embedded within a matrix of extracellular substance. Biofilms also pose a therapeutic impediment and are notoriously difficult to treat. As such, S. aureus is designated by the WHO as a high priority pathogen for development of new antibiotics. With an increasing number of vulnerable people in society, it is imperative to discover new drugs effective against organisms such as S. aureus.

Project summary

The goal of this proposal is to overcome resistance to antibiotics, targeting the biosynthesis of lipoteichoic acids (LTA), membrane glycopolymers integral to the survival of Gram-positive bacteria (S. aureus) and in the formation of biofilms. Specifically, we will inhibit two novel targets: lipoteichoic acid synthase (LtaS) and
 the D-alanine:D-alanyl carrier protein ligase
(DltA). 

Our specific aims are:

  • Make strategic functional group replacements of a lead compound, inhibitor of LtaS,
  • Assess the antimicrobial and antibiofilm (preventative and curative) activity of new LtaS inhibitors and of a in-house library of amino acid sulfamoyl derivatives of D-AlaSA, a DltA inhibitor.
  • Assess the compounds for synergy with anti-staphylococcal host factors (fatty acids, antimicrobial peptides) and established cationic antibiotics (daptomycin), to determine if combinations of therapeutics can be identified.
  • To test the probability of antimicrobial resistance arising over time, and to examine phenotypic responses, through real-time diffusion-mutation assays and microfluidic single-cell experiments.

To study using microfluidics the phenotypic responses of bacteria towards the compounds (heterogeneity in growth and killing, and formation of persister cell reservoirs), which will deliver a refined measure of the minimum inhibitory concentration.

Community site (GW4 Portal)