Influence of copper on the appearance of antimicrobial persistence or tolerance in Mycobacterium tuberculosis and Mycobacterium africanum

• Grant number: 23/07582-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2023
• End date: November 30, 2027
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Ana Marcia de Sá Guimarães
• Grantee: Kevim Bordignon Guterres
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Tuberculosis is a serious infectious disease that has a long treatment period and variable response. One cause of difficult treatment is the ability of mycobacteria to vary phenotypically, enabling them to tolerate drug exposure or select treatment-persistent subpopulations. The mechanisms that lead to this phenotypic variation have not been fully elucidated. It is believed that changes in the cellular microenvironment significantly contribute to this phenotypic modulation. In this context, nutritional immunity occurs when the host manipulates levels of metabolites and ions, such as metals, to fight pathogens. During Mycobacterium tuberculosis (Mtb) infection, copper plays an important role, and its excess can lead to oxidative stress and loss of protein function. Copper exposure may also be related to drug tolerance in bacteria due to metal-induced oxidative stress. Our laboratory has recently identified a defect in copper homeostasis in Mycobacterium africanum (Maf), an Mtb-related ecotype of public health importance. Thus, the study aims to investigate whether copper contributes to the emergence of tolerance and persistence to antibiotics (rifampicin, isoniazid, and moxifloxacin) in Mtb and Maf strains 5 and 6. We will investigate whether these phenomena can be explained by changes in bacterial replication and/or cell wall permeability to drugs due to modulation of lipid composition. Furthermore, we intend to determine global gene profiles of response to copper toxicity in Mtb and Maf, verifying mechanisms of changes in bacterial replication and/or lipid metabolism, combined with the evaluation of dormancy markers. (AU)