Antimicrobial Peptide against Mycobacterium Tuberculosis That Activates Autophagy Is an Effective Treatment for Tuberculosis.

Abstract

Mycobacterium tuberculosis (MTB) is the principal cause of human tuberculosis (TB), which is a serious health problem worldwide. The development of innovative therapeutic modalities to treat TB is mainly due to the emergence of multi drug resistant (MDR) TB. Autophagy is a cell-host defense process. Previous studies have reported that autophagy-activating agents eliminate intracellular MDR MTB. Thus, combining a direct antibiotic activity against circulating bacteria with autophagy activation to eliminate bacteria residing inside cells could treat MDR TB. We show that the synthetic peptide, IP-1 (KFLNRFWHWLQLKPGQPMY), induced autophagy in HEK293T cells and macrophages at a low dose (10 μM), while increasing the dose (50 μM) induced cell death; IP-1 induced the secretion of TNFα in macrophages and killed Mtb at a dose where macrophages are not killed by IP-1. Moreover, IP-1 showed significant therapeutic activity in a mice model of progressive pulmonary TB. In terms of the mechanism of action, IP-1 sequesters ATP in vitro and inside living cells. Thus, IP-1 is the first antimicrobial peptide that eliminates MDR MTB infection by combining four activities: reducing ATP levels, bactericidal activity, autophagy activation, and TNFα secretion.

• Authors: Erika A Peláez Coyotl, Jacqueline Barrios Palacios, Gabriel Muciño, Daniel Moreno-Blas, Miguel Costas, Teresa Montiel Montes, Christian Diener, Salvador Uribe-Carvajal, Lourdes Massieu, Susana Castro-Obregón, Octavio Ramos Espinosa, Dulce Mata Espinosa, Jorge Barrios-Payan, Juan Carlos León Contreras, Gerardo Corzo, Rogelio Hernández-Pando, Gabriel Del Rio
• Journal: Pharmaceutics (Pharmaceutics) Vol. 12 Issue 11 (Nov 09 2020) ISSN: 1999-4923 [Print] Switzerland
• PMID: 33182483 (Publication Type: Journal Article)