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

Author:

Peláez Coyotl Erika A.,Barrios Palacios Jacqueline,Muciño Gabriel,Moreno-Blas DanielORCID,Costas MiguelORCID,Montiel Montes Teresa,Diener Christian,Uribe-Carvajal Salvador,Massieu Lourdes,Castro-Obregón SusanaORCID,Espinosa Octavio RamosORCID,Mata Espinosa Dulce,Barrios-Payan Jorge,León Contreras Juan CarlosORCID,Corzo GerardoORCID,Hernández-Pando Rogelio,Del Rio GabrielORCID

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.

Publisher

MDPI AG

Subject

Pharmaceutical Science

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