Rufomycin Exhibits Dual Effects Against Mycobacterium abscessus Infection by Inducing Host Defense and Antimicrobial Activities.

Cho Rong Park,Jinhua Cheng,Jake Whang,Sanghyun Cho,Seungwha Paik,Guido F Pauli,Sang Min Jeon,Young Jae Kim,Joo-Won Suh,Eun-Kyeong Jo,Gauri Shetye,James Mcalpine,Sang-Hee Lee,Shao-Nong Chen,Jin Kyung Kim,Jin Cao,Scott Franzblau

doi:10.3389/fmicb.2021.695024

Abstract

Nontuberculous mycobacterial pulmonary infection is often aggravated due to antibiotic resistance issues. There is a need for development of new drugs inducing both host immune responses and antimicrobial activities. This study shows that the rufomycins 4/5/6/7 (Rufomycin 4–7), which targets ClpC1 as a subunit of caseinolytic protein complex ClpC1/ClpP1/ClpP2 of mycobacteria, exhibits a dual effect in host innate defense and in vivo antimicrobial activities against a rough morphotype of Mycobacterium abscessus (Mabs-R), a clinically severe morphotype that causes hyperinflammation. Rufomycin 4–7 treatment showed antimicrobial effects against Mabs pulmonary infection in vivo and in macrophages. In addition, Rufomycin 4–7 significantly decreased inflammation, but enhanced the autophagy/lysosomal genes through upregulation of the nuclear translocation of transcription factor EB (TFEB). Furthermore, Rufomycin 4–7 treatment effectively inhibited mitochondrial damage and oxidative stresses in macrophages during Mabs-R infection. Collectively, Rufomycin 4–7-mediated dual effects inducing both antimicrobial activities and host immune defense might confer an advantage to treatment against Mabs-R infection.

Highlights

Nontuberculous mycobacteria (NTM) are a diverse group of more than 190 bacilli, other than Mycobacterium tuberculosis complex (Porvaznik et al, 2017)
The present study provides evidence that Rufomycin 4–7 exhibits a dual mode of action by inducing antimicrobial responses and host defense
While Rufomycin 4–7 is a well-founded potential lead compound essential for M. tuberculosis (Mtb) and Mycobacterium abscessus subsp. abscessus (Mabs)-S through targeting ClpC1 of mycobacteria (Choules et al, 2019), it is largely unknown whether Rufomycin 4–7 regulates host protective immune responses

Summary

Introduction

Nontuberculous mycobacteria (NTM) are a diverse group of more than 190 bacilli, other than Mycobacterium tuberculosis complex (Porvaznik et al, 2017). NTM are ubiquitously found in the environments, some of them are able to cause disease in immunocompetent and immunocompromised persons (Simons et al, 2011; Wassilew et al, 2016; Porvaznik et al, 2017; Maiz Carro et al, 2018; Sethiya et al, 2020). NTM can cause a wide range of human infections, and the most common clinical feature is a chronic pulmonary infection (Simons et al, 2011; Wassilew et al, 2016; Maiz Carro et al, 2018; To et al, 2020). There is an urgent need for novel host-directed therapeutic approaches that boost host defense pathways as well as target Mabs pathogens, thereby decreasing the prospect of pathogens developing resistance during treatment

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Results

Conclusion