CNC

Overview

Project Summary

Antibiotics shaped modern medicine, increasing the average life expectancy and helping to transfer the burden of death from communicable to non-communicable diseases (cardiovascular disease, stroke, cancer, diabetes, etc.). However, the increasing resistance of pathogens to several classes of antibiotics, while so few are introduced to clinical use, threatens these advances, with antimicrobial resistance (AMR)-related deaths already having reached an estimated 4.95 million in 2019.

In the golden era of antibiotic discovery, extensive phenotypic screening of antimicrobial-producing organisms originated various new antibiotic classes. When obvious sources of natural antimicrobials were nearly exhausted, the advent of the genomics era promoted synthetic and target-based drug discovery approaches as a revolution in antibiotic research. Nevertheless, they were outperformed by the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs. Now a more flexible combination approach is regarded as advisable when searching for antimicrobial compounds. In the fight against AMR, it is necessary to discover traditional small molecules, alongside non-traditional approaches that target specific microorganisms or their toxins.

Diabetes is one of the fastest rising diseases in the world. Diabetic patients present vasculopathy, neuropathy and altered skin metabolism, often leading to formation of foot wounds known as diabetic foot ulcers (DFU). 10–15% DFUs become chronic and ~30% will lead to lower extremity amputation, having a 5-year mortality rate of 50%. Infected and chronic DFUs present poor therapeutic outcomes and are a great burden on healthcare systems. Microbial colonization, biofilm formation and infection are hypothesized to impair healing and contribute to increased risk of amputation.

Successful treatment of infected DFUs involves proper wound care and the administration of systemic antibiotic therapy. Antibiotics’ limited efficiency against a biofilm laden polymicrobial wound, combined with multiple hospitalizations for recurrent DFUs, create great challenges and subsequent multi drug resistance (MDR). It is therefore urgent to find better therapeutics for DFU management, including more effective antibiotics.

The aim of this project is to identify relevant conditions of microbial interactions between commensal skin bacteria and DFU isolates of clinical significance and to detect compounds with promising antimicrobial activity against these isolates. We propose to (i) identify culture conditions and strains producing inhibitor compounds by co-culture competition assays; (ii) identify the candidate metabolites produced by MS/NMR; (iii) sequence the genome of inhibited strains and producers to find the responsible biosynthetic gene clusters and/or other targetable resistance mechanisms; (iv) in silico disclose the molecular targets of the observed antimicrobial effect and predict toxicity, mutagenicity and carcinogenicity.

This project will help secure future therapies for DFU management, ensuring healthy lives and promoting well-being for all at all ages, a main goal for the United Nations (UN) 2030 Agenda for Sustainable Development.

Main Goals

Detect compounds with promising antimicrobial activity against DFU isolates. Find the responsible biosynthetic gene clusters and/or other targetable resistance mechanisms; and in silico disclose the molecular targets of the observed antimicrobial effect.