A double mutant of Mycobacterium tuberculosis targeting membrane transporters CtpF and MmpL7 as a promising live-attenuated vaccine candidate

Title : A double mutant of Mycobacterium tuberculosis targeting membrane transporters CtpF and MmpL7 as a promising live-attenuated vaccine candidate

Abstract:

Tuberculosis (TB) remains the leading cause of death from a bacterial pathogen worldwide, and the limited efficacy of the century-old Mycobacterium bovis Bacillus Calmette–Guérin (BCG) vaccine underscores the urgent need for novel, rationally designed vaccines capable of inducing durable protection. Previous studies have identified the P-type ATPase CtpF as a validated attenuation target in Mycobacterium tuberculosis (Mtb), given its essential role in calcium transport, oxidative stress response, and intracellular survival. Mutants lacking ctpF display significant attenuation in both cellular and animal models, confirming its role in virulence.

Building upon this evidence, single deletion mutants, MtbH37RvΔctpF and MtbH37RvΔmmpL7, were constructed (ΔmmpL7) and characterized to assess their phenotypic and molecular features. Both mutant strains displayed phenotypic traits commonly associated with attenuation in Mtb, including changes in colony morphology, reduced surface hydrophobicity, and alterations in the composition of cell envelope lipids—particularly in PDIMs, TDMs, and PIMs, the first two being well-recognized virulence factors.

These findings guided the rational construction of a double mutant, MtbH37RvΔctpFΔmmpL7, devoid of antibiotic resistance markers and preserving the secretion of ESAT-6 and CFP-10, two major immunomodulatory antigens essential for host immune recognition. The combination of reduced virulence, cell envelope remodelling, and maintenance of major immunomodulatory antigens highlights the MtbH37RvΔctpFΔmmpL7 strain as a promising candidate for next-generation live-attenuated vaccine against TB.

Biography:

Carlos-Yesid Soto is a Full Professor at the National University of Colombia, where he leads the research group Biochemistry and Molecular Biology of Mycobacteria. He holds an M.Sc. in Microbiology and a Ph.D. in Biological Sciences from the Universitat Autònoma de Barcelona, with postdoctoral training at the University of Zaragoza. His research focuses on biomarkers of mycobacterial virulence and latency, P-type ATPases as targets for attenuation and vaccine design, and novel antitubercular compounds. Professor Soto served as President of the Latin American Society of Tuberculosis and Other Mycobacteriosis - SLAMTB (2020–2023).