New Screening method for Antibiotic Discovery Pipeline

An alarming number of bacteria are becoming resistant to front-line therapies. However, only yet few new antibiotics have reached the market in the last five decades. Although identifying agents that kill bacteria is a relatively straightforward process, determining just how a chemical exerts its mode of action is often time-consuming and expensive, hindering drug development as world famous antibiotic experts will point out in March at a meeting in Berlin.

Now, a Swiss-French-Hungarian research team has developed a high-throughput method to systematically quantify and interpret dynamic metabolome responses of mycobacteria to new antimicrobial compounds. The group headed by Matt Zampieri from ETH Zurich demonstrate how one can infer the mode of action of uncharacterized antimycobacterial compounds by comparing drug-induced metabolic responses in Mycobacterium smegmatis, a close realative to M tuberculosis. Their combined mass spectrometry-based metabolomics and computational workflow scaled with the size of typical compound libraries and hence could facilitate the selection of antimicrobial compound leads with potentially new modes of action.

Reasoning that subtle alterations within the vast array of molecules that bacteria produce as part of their metabolism might offer insight into the mode of action for a drug, Zampieri and colleagues exposed Mycobacterium smegmatis to multiple doses of 62 reference compounds with known activities and profiled metabolomes at seven different timepoints. After developing a computational framework for parsing out predicted modes of actions based on pairwise comparisons between known chemicals,Zampieri et al. applied their platform to 212 uncharacterised compounds that emerged from a large-scale screenof GlaxoSmithKline for anti-tuberculosis agents.

More than 70% of these new compounds induced metabolic responses in M. smegmatis indicative of known MoAs. Only 8% (16) of the compounds appeared to target unconventional cellular processes, illustrating the difficulty in discovering new antibiotics with different MoAs among compounds used as monotherapies. Six compounds exerted anti-tuberculosis effects through a previously uncovered pathway involving trehalose and lipid metabolism. This was supported by whole-genome sequencing of spontaneous drug-resistant mutants of the pathogen Mycobacterium tuberculosis and in vitro compound-proteome interaction analysis for one of these compounds. The authors note that expanding their analysis to other types of bacteria and even more compounds could pave the way to new opportunities for antibiotic discovery.