Rational Design of Biosafety Level 2-Approved, Multidrug-Resistant Strains of Mycobacterium tuberculosis through Nutrient Auxotrophy

MBio
Catherine VilchèzeWilliam R Jacobs

Abstract

Multidrug-resistant (MDR) tuberculosis, defined as tuberculosis resistant to the two first-line drugs isoniazid and rifampin, poses a serious problem for global tuberculosis control strategies. Lack of a safe and convenient model organism hampers progress in combating the spread of MDR strains of Mycobacterium tuberculosis We reasoned that auxotrophic MDR mutants of M. tuberculosis would provide a safe means for studying MDR M. tuberculosis without the need for a biosafety level 3 (BSL3) laboratory. Two different sets of triple auxotrophic mutants of M. tuberculosis were generated, which were auxotrophic for the nutrients leucine, pantothenate, and arginine or for leucine, pantothenate, and methionine. These triple auxotrophic strains retained their acid-fastness, their ability to generate both a drug persistence phenotype and drug-resistant mutants, and their susceptibility to plaque-forming mycobacterial phages. MDR triple auxotrophic mutants were obtained in a two-step fashion, selecting first for solely isoniazid-resistant or rifampin-resistant mutants. Interestingly, selection for isoniazid-resistant mutants of the methionine auxotroph generated isolates with single point mutations in katG, which encodes an isoniazid-activ...Continue Reading

References

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Citations

Jul 8, 2020·Antimicrobial Agents and Chemotherapy·Catherine VilchèzeWilliam R Jacobs
Jan 27, 2019·Nature Reviews. Immunology·David G RussellBrian C VanderVen
May 3, 2019·Science Translational Medicine·Steven A Porcelli, William R Jacobs
Jan 17, 2021·International Journal of Molecular Sciences·Anna Allué-GuardiaJordi B Torrelles
Jul 28, 2019·Microbiology Spectrum·Gabriel T MashabelaDigby F Warner
Jul 31, 2019·Accounts of Chemical Research·Timothy J de WetValerie Mizrahi
Jul 20, 2021·Antimicrobial Agents and Chemotherapy·Loes van SchieNico Callewaert

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Methods Mentioned

BETA
Infection
Scanning electron microscopy
flow cytometry
PCR

Software Mentioned

FlowJo

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