New strategies for breaking intrinsic antibiotic resistance of mycobacteria

Research Project, 2025 – 2029

Tuberculosis is one of the deadliest infectious diseases and new treatments are urgently needed. Mycobacteria are highly intrinsically resistant due to their impermeable mycolic acid layer (MA), precluding the use of most antibiotics.My group has discovered that mycobacterial genomes encode peptide sequences that selectively permeabilize their own MA (MA-permeabilizing peptides = MAPPs). We could provide the proof-of-concept that MAPPs drastically potentiate the activity of drugs that would otherwise not be active. We have further observed that they are most effective against their own source organism, suggesting that MAPPs can be finetuned to be species-specific. Here, the potential of these innate peptides as new leads for antitubercular potentiators will be investigated.We will mine mycobacterial genomes for MAPPs and test them for their MA activity, selectivity, cyto- and acute toxicity. Using mycobacterial cytological profiling, the mechanisms underlying MA selectivity and their structure-activity relationship will be studied. Finally, both their in vitro and in vivo synergy with antibiotics and antimicrobial peptides will be assessed.MAPPs could make a broad spectrum of antibiotics available for treating tuberculosis and may additionally act as immune boosters. Their impressive synergy together with the potential to make them species-specific promise drastic lowering of antibiotic doses and could thus considerably mitigate side effects on patients and their microbiome.