Redox Cycling Dioxonaphthoimidazoliums Disrupt Iron Homeostasis in Mycobacterium bovis Bacillus Calmette-Guérin

TY - JOUR

T1 - Redox Cycling Dioxonaphthoimidazoliums Disrupt Iron Homeostasis in Mycobacterium bovis Bacillus Calmette-Guérin

AU - Li, Ming

AU - Yamada, Yoshiyuki

AU - Rodriguez, G. Marcela

AU - Dick, Thomas

AU - Go, Mei Lin

N1 - Publisher Copyright: © 2022 Li et al.

PY - 2022/11

Y1 - 2022/11

N2 - The dioxonaphthoimidazolium scaffold is a novel, highly bactericidal redox cycling antituberculosis chemotype that is reliant on the respiratory enzyme Type II NADH dehydrogenase (NDH2) for the generation of reactive oxygen species (ROS). Here, we employed Mycobacterium bovis Bacillus Calmette-Guérin (M. bovis BCG) reporter strains to show that ROS generated by the redox cycler SA23 simulated an iron deficient state in the bacteria, which led to a compensatory increase in the expression of the iron acquisition mbtB gene while collaterally reducing the expression of the iron storage bfrB gene. Exacerbating the iron deficiency via the inclusion of an iron chelator or aggravating oxidative stress by deploying a catalase (KatG) loss-of-function mutant strain enhanced the activity of SA23, whereas a combined approach of treating the katG mutant strain with an iron chelator led to even greater gains in activity. Our results support the notion that the activity of SA23 pivots on a vicious cycle of events that involve the derailment of iron homeostasis toward greater acquisition of the metal, overwhelmed oxidative stress defenses due to enhanced Fenton reactivity, and, ultimately, self-inflicted death. Hence, we posit that redox cyclers that concurrently perturb the iron equilibrium and cellular respiration are well-positioned to be potent next-generation anti-tubercular drugs.

AB - The dioxonaphthoimidazolium scaffold is a novel, highly bactericidal redox cycling antituberculosis chemotype that is reliant on the respiratory enzyme Type II NADH dehydrogenase (NDH2) for the generation of reactive oxygen species (ROS). Here, we employed Mycobacterium bovis Bacillus Calmette-Guérin (M. bovis BCG) reporter strains to show that ROS generated by the redox cycler SA23 simulated an iron deficient state in the bacteria, which led to a compensatory increase in the expression of the iron acquisition mbtB gene while collaterally reducing the expression of the iron storage bfrB gene. Exacerbating the iron deficiency via the inclusion of an iron chelator or aggravating oxidative stress by deploying a catalase (KatG) loss-of-function mutant strain enhanced the activity of SA23, whereas a combined approach of treating the katG mutant strain with an iron chelator led to even greater gains in activity. Our results support the notion that the activity of SA23 pivots on a vicious cycle of events that involve the derailment of iron homeostasis toward greater acquisition of the metal, overwhelmed oxidative stress defenses due to enhanced Fenton reactivity, and, ultimately, self-inflicted death. Hence, we posit that redox cyclers that concurrently perturb the iron equilibrium and cellular respiration are well-positioned to be potent next-generation anti-tubercular drugs.

KW - Mycobacterium bovis BCG

KW - ROS

KW - iron homeostasis

KW - redox cycling

UR - https://www.scopus.com/pages/publications/85144638282

U2 - 10.1128/spectrum.01970-22

DO - 10.1128/spectrum.01970-22

M3 - Article

C2 - 36377959

SN - 2165-0497

VL - 10

JO - Microbiology spectrum

JF - Microbiology spectrum

IS - 6

ER -