Abstract
BackgroundTuberculosis (TB) is one of the most prevalent infectious diseases affecting millions worldwide. The currently available anti-TB drugs and vaccines have proved insufficient to contain this scourge, necessitating an urgent need for identification of novel drug targets and therapeutic strategies. The disruption of crucial protein-protein interactions, especially those that are responsible for virulence in Mycobacterium tuberculosis – for example the ESAT-6:CFP10 complex – are a worthy pursuit in this direction.MethodsWe therefore sought to improvise a method to attenuate M. tuberculosis while retaining the latter’s antigenic properties. We screened peptide libraries for potent ESAT-6 binders capable of dissociating CFP10 from ESAT-6. We assessed the disruption by a peptide named HCL2, of the ESAT-6:CFP10 complex and studied its effects on mycobacterial survival and virulence.ResultsWe found that HCL2, derived from the human cytochrome c oxidase subunit 3 (COX3) protein, disrupts ESAT-6:CFP10 complex, binds ESAT-6 potently, disintegrates bacterial cell wall and inhibits extracellular as well as intracellular mycobacterial growth. In addition, an HCL2 expressing M. tuberculosis strain induces both Th1 and Th17 host protective responses.ConclusionsDisruption of ESAT-6:CFP10 association could, therefore, be an alternate method for attenuating M. tuberculosis, and a possible route towards future vaccine generation.
Highlights
Tuberculosis (TB) is one of the most prevalent infectious diseases affecting millions worldwide
We have demonstrated that disruption of ESAT-6:CFP10 attenuates virulence in M. tuberculosis rendering faster clearance in mice
Additional file 4: Figure S4. (A) Intraperitoneal macrophages isolated from mice were cultured and, 10 hours post-infection with H37Rv and H37Rv/HCL2 strains in 1:10 ratio, were surface-stained with anti-CD11B, CD11C antibodies followed by Annexin V staining for 40 min followed by flow cytometry to assess pre apoptotic cells
Summary
Tuberculosis (TB) is one of the most prevalent infectious diseases affecting millions worldwide. The disruption of crucial protein-protein interactions, especially those that are responsible for virulence in Mycobacterium tuberculosis – for example the ESAT-6: CFP10 complex – are a worthy pursuit in this direction. There exist no peptides or small molecules that target bacterial virulence factors Such moieties can conveniently be used along with conventional drugs to improve TB chemotherapy and in combating multi-drug resistance [9]. RD-1 recombinant BCG generates both Th1 and Th17 responses, this strain is unsuitable as a vaccine because RD-1 addition makes BCG virulent [10]. It was, our aim to elucidate the role of interaction between RD-1 components and their potential therapeutic interventions
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