These antibiotics are mostly derived from soil bacteria, often Streptomyces ( Clardy et al., 2009 Genilloud, 2017).
Our clinical antibacterial arsenal is composed to a large extent of natural products or their semi-synthetic derivatives. Thus, IPA is a microbial metabolite that inhibits growth of other microbes and therefore represents an antibiotic in the classical sense ( Negatu et al., 2018). Recently, several IPA producing gut-dwelling clostridia and Peptostreptococcus anaerobius were identified, and the biosynthetic pathway of IPA production from tryptophan was elucidated ( Dodd et al., 2017). Interestingly, IPA is a metabolite produced by gut bacteria ( Dodd et al., 2017). IPA showed no activity against Gram-negative or -positive bacteria, and thus appears to display selective but broad spectrum antimycobacterial activity ( Negatu et al., 2018, 2019). Using a mouse model of TB infection, we demonstrated in vivo efficacy ( Negatu et al., 2018). The compound showed anti-TB (including multi-drug resistant Mycobacterium tuberculosis) and anti-NTM (including Mycobacterium avium) activity in vitro. Screening the R03 library resulted in the identification of indole propionic acid (IPA) as a new antimycobacterial ( Negatu et al., 2018). This lesion-pharmacokinetic property contributes to the remarkable clinical efficacy of pyrazinamide, despite the drug’s moderate in vitro potency ( Dartois, 2014 Prideaux et al., 2015). Thus, fragment-sized TB drugs effectively reach all mycobacterial populations sequestered in various lesion compartments ( Prideaux et al., 2015). The physicochemical properties associated with their size makes these small drugs effective penetrators of lung lesions associated with mycobacterial diseases. It is interesting to note that several anti-TB drugs, such as pyrazinamide and isoniazid, are fragment-sized drugs ( Jhoti et al., 2013 Riccardi and Pasca, 2014). Typically, R03 libraries are employed for structure-based drug discovery approaches in which hits are either grown or connected to generate high affinity binders ( Jhoti et al., 2013). However, R03 compounds constitute attractive starting points for lead optimization ( Jhoti et al., 2013 Gopal and Dick, 2014). Due to their small size and the resulting limited molecular interaction surface, R03 compliant compounds are expected to show poor on-target activity. R03 compliant compounds are “fragment”-sized (i.e., molecular weight <300 g/mol), have a cLogP of ≤3, and the number of hydrogen bond donors and acceptors is ≤3 ( Jhoti et al., 2013). 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). 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. In addition to its antimycobacterial activity, the molecule displays anti-inflammatory and antioxidant properties. 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. Thus, the microbiota in our gut may influence susceptibility to mycobacterial diseases. Interestingly, the microbiota-produced metabolite is detectable in the serum of healthy individuals, tuberculosis (TB) patients, and several animal models. IPA is active against a broad spectrum of mycobacteria, including drug resistant Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM). The molecule is small, chemically tractable, and targets amino acid biosynthesis. IPA is produced by the human gut microbiota. Here, we discuss discovery, mechanism of action, and the therapeutic potentials of an unusual antibiotic, indole propionic acid (IPA). These natural products are often large and suffer from poor chemical tractability. Most antibiotics are produced by soil microbes and typically interfere with macromolecular synthesis processes as their antibacterial mechanism of action.
3Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, United States.2Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States.
1Center for Innovative Drug Development and Therapeutic Trials for Africa, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.Dereje Abate Negatu 1,2, Martin Gengenbacher 2,3, Véronique Dartois 2,3 and Thomas Dick 2,3,4 *