Peláez Coyotl Erika A, Barrios Palacios Jacqueline, Muciño Gabriel, Moreno-Blas Daniel, Costas Miguel, Montiel Montes Teresa, Diener Christian, Uribe-Carvajal Salvador, Massieu Lourdes, Castro-Obregón Susana, Espinosa Octavio Ramos, Mata Espinosa Dulce, Barrios-Payan Jorge, León Contreras Juan Carlos, Corzo Gerardo, Hernández-Pando Rogelio, Del Rio Gabriel
Department of Biochemistry and Structural Biology, Institute of Cellular Physiology, National Autonomous University of Mexico (UNAM), 04510 Mexico City, Mexico.
Experimental Pathology Section, National Institute of Medical Sciences and Nutrition Salvador Zubirán, 14080 Mexico City, Mexico.
Pharmaceutics. 2020 Nov 9;12(11):1071. doi: 10.3390/pharmaceutics12111071.
(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.
结核分枝杆菌（MTB）是人类结核病（TB）的主要病因，结核病是全球严重的健康问题。开发创新的结核病治疗方法主要是由于多重耐药（MDR）结核病的出现。自噬是一种细胞宿主防御过程。先前的研究报道，自噬激活剂可消除细胞内的多重耐药MTB。因此，将针对循环细菌的直接抗生素活性与自噬激活相结合以消除细胞内的细菌，可以治疗多重耐药结核病。我们发现，合成肽IP-1（KFLNRFWHWLQLKPGQPMY）在低剂量（10μM）时可诱导HEK293T细胞和巨噬细胞发生自噬，而增加剂量（50μM）则会诱导细胞死亡；IP-1在巨噬细胞中诱导TNFα的分泌，并在不杀死巨噬细胞的剂量下杀死结核分枝杆菌。此外，IP-1在进行性肺结核小鼠模型中显示出显著的治疗活性。就作用机制而言，IP-1在体外和活细胞内螯合ATP。因此，IP-1是第一种通过结合降低ATP水平、杀菌活性、自噬激活和TNFα分泌这四种活性来消除多重耐药MTB感染的抗菌肽。
