Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, With Anti-inflammatory and Antioxidant Properties.

Martin Gengenbacher,Véronique Dartois,Dereje Abate Negatu,Thomas Dick

doi:10.3389/fmicb.2020.575586

Abstract

Most antibiotics are produced by soil microbes and typically interfere with macromolecular synthesis processes as their antibacterial mechanism of action. These natural products are often large and suffer from poor chemical tractability. Here, we discuss discovery, mechanism of action, and the therapeutic potentials of an unusual antibiotic, indole propionic acid (IPA). IPA is produced by the human gut microbiota. The molecule is small, chemically tractable, and targets amino acid biosynthesis. IPA is active against a broad spectrum of mycobacteria, including drug resistant Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM). Interestingly, the microbiota-produced metabolite is detectable in the serum of healthy individuals, tuberculosis (TB) patients, and several animal models. Thus, the microbiota in our gut may influence susceptibility to mycobacterial diseases. If a gut-lung microbiome axis can be demonstrated, IPA may have potential as a biomarker of disease progression, and development of microbiota-based therapies could be explored. In addition to its antimycobacterial activity, the molecule displays anti-inflammatory and antioxidant properties. This raises the possibility that IPA has therapeutic potential as both antibiotic and add-on host-directed drug for the treatment of TB in patient populations where disease morbidity and mortality is driven by excessive inflammation and tissue damage, such as TB-associated immune reconstitution inflammatory syndrome, TB-meningitis, and TB-diabetes.

Highlights

To identify chemical starting points for the discovery of new drugs against resistant tuberculosis (TB) and lung disease caused by non-tuberculous mycobacteria (NTM), we recently screened a library of rule-of-3 (R03) compliant compounds for whole cell actives (Negatu et al, 2018)
Through structural modeling followed by metabolic, genetic, and biochemical analyses, we demonstrated that indole propionic acid (IPA) blocks tryptophan biosynthesis by binding to the allosteric tryptophan binding site of TrpE, shutting down the enzyme’s activity (Figure 1; Negatu et al, 2019)
In a series of reports, IPA has been suggested to play a protective role against Type II diabetes, the major type of diabetes associated with TB

Summary

Introduction

To identify chemical starting points for the discovery of new drugs against resistant tuberculosis (TB) and lung disease caused by non-tuberculous mycobacteria (NTM), we recently screened a library of rule-of-3 (R03) compliant compounds for whole cell actives (Negatu et al, 2018). The discovery of IPA’s antimycobacterial activity may provide the missing functional link between gut bacteria and mycobacterial lung disease (Figure 1). IPA can be detected in the serum of animal models, which are used to study mycobacterial lung disease, such as mice and rabbits (Wikoff et al, 2009; Kennedy et al, 2018; unpublished observations by the authors).

Results

Conclusion