Tuberculosis is a chronic infectious disease usually caused by Mycobacterium tuberculosis (M. tuberculosis) bacteria. 80% of tuberculosis occurs in the lungs, and other organs (cervical lymph, meninges, peritoneum, intestinal skin, bone) can also be secondary infected. Respiratory transmission is the main mode of tuberculosis transmission. Its symptoms are low fever, fatigue, cough and hemoptysis. Since the discovery of streptomycin in 1943, many additional compounds to combat tuberculosis have been introduced. These agents include natural products such as Rifampicin as well as synthetic antibiotics. Despite these advances, tuberculosis remains a major infectious disease, killing millions of people each year. However, the inclusion of broad-spectrum compounds in current tuberculosis regimens precludes the use of selectively acting anti-M. tuberculosis antibiotics. Therefore, the development of a highly selective anti-tuberculosis antibiotic is particularly important. Here, we will introduce a selective anti-M. tuberculosis agent, Evybactin.

Evybactin is a cyclic depsipeptide DNA gyrase inhibitor with an antimicrobial effect.

From: Imai Y, Lewis K, et al. Nat Chem Biol. 2022 Aug 22.

Especially, Evybactin potently and selectively kills M. tuberculosis, with a MIC value of 0.25 µg/mL. Meanwhile, Evybactin shows no activity against Lactobacillus sp. and Bacteroides sp. Additionally, Evybactin shows no toxicity against HepG2, FaDu and HEK293 human cells. Moreover, in a mouse model of septicemia infection with E. coli, Evybactin (25-100 mg/kg; i.p.) protects mice from E. coli infection. In addition, Evybactin targets DNA gyrase and binds to a site overlapping with synthetic thiophene poisons. Mechanistically, Evybactin smuggles into M. tuberculosis by a promiscuous transporter of hydrophilic compounds, BacA. Specifically, in E. coli, Evybactin is transported into the cell by SbmA but efficiently effluxed by TolC-dependent multidrug resistances (MDRs). The Gram-positive M. tuberculosis lacks a similar restrictive penetration barrier and, as a result, is sensitive to Evybactin, which is transported into the cell by BacA.

To sum up, Evybactin is a cyclic depsipeptide DNA gyrase inhibitor that potently and selectively against M. tuberculosis.

References:

[1] Yu Imai, et al. Nat Chem Biol. 2022 Aug 22.

[2] Imai Y, Lewis K, et al. Nat Chem Biol. 2022 Aug 22.