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Staphylococcal Infections · Journal article
Virulence · August 30, 2026
Raises a question worth testing. It does not answer one.
This mechanistic study demonstrates that cryptotanshinone selectively inhibits Staphylococcus aureus NdhC (NDH-2 isoform) through uncompetitive inhibition against the quinone substrate and identifies threonine T352 as a critical binding residue. The work shows collateral sensitivity in gentamicin-induced and menaquinone-auxotrophic small colony variants in vitro, suggesting a potential strategy for targeting antibiotic-tolerant bacterial populations, but lacks clinical evidence of efficacy.
In vitro mechanistic study with molecular docking, site-directed mutagenesis, and bacterial susceptibility assays. Staphylococcus aureus laboratory strains, including wild-type and mutant derivatives; small colony variants generated by gentamicin induction or carrying menC frameshift mutations conferring menaquinone auxotrophy. Intervention: Cryptotanshinone (98% HPLC purity) administered to bacterial cultures and isolated membrane preparations; ndhC and ndhF gene overexpression via plasmid; site-directed mutagenesis of NdhC. Compared with: Wild-type strains; ndhF overexpressing strains; strains lacking cryptotanshinone treatment. College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
ndhC overexpression doubled bacterial sensitivity to cryptotanshinone, while ndhF overexpression had no effect Cryptotanshinone exhibits noncompetitive inhibition against NADH and uncompetitive inhibition against menadione in NdhC Threonine T352 identified as critical for cryptotanshinone binding to the NdhC-menadione complex via molecular docking and site-directed mutagenesis
Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.
This work is preclinical and exploratory. While it characterizes a potentially novel antimicrobial target and describes collateral sensitivity in antibiotic-tolerant variants, no human or animal efficacy data are presented; further translational studies would be required to evaluate clinical utility.
This is a mechanistic study using in vitro enzymatic assays, molecular docking, and site-directed mutagenesis to characterize cryptotanshinone's inhibition of bacterial NADH dehydrogenase; it raises questions about therapeutic potential rather than demonstrating clinical efficacy.
As stated by the source record.
Quoted from the source exactly as published.
This work is preclinical and exploratory. While it characterizes a potentially novel antimicrobial target and describes collateral sensitivity in antibiotic-tolerant variants, no human or animal efficacy data are presented; further translational studies would be required to evaluate clinical utility.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Staphylococcus aureus small colony variants (SCVs) pose a clinical challenge due to antibiotic tolerance and recurrent infections. Targeting the bacterial respiratory chain offers a potential strategy to overcome SCV-mediated resistance. Here we show that cryptotanshinone (CT) selectively inhibits S. aureus's NDH-2 isoform NdhC. Antimicrobial assays showed that ndhC overexpression doubled bacterial sensitivity to CT, while ndhF overexpression had no effect. In vitro enzymatic analysis indicated that CT inhibits NdhC, with noncompetitive inhibition against NADH and uncompetitive inhibition against menadione (MD). Molecular docking and site-directed mutagenesis identified threonine T352 as critical for CT binding to the NdhC-MD complex. Using membrane vesicle assays and cellular thermal shift assays, we obtained evidence that CT acts at NdhC in isolated membrane preparations in a substrate-dependent manner. Notably, gentamicin-induced SCVs carrying fusA and perR mutations exhibited collateral sensitivity to NDH-2 inhibitors. Further characterization of menaquinone (MK) auxotrophic SCVs, which harbor a frameshift mutation in menC and show reduced but detectable NADH dehydrogenase activity, revealed that these variants also display heightened susceptibility to CT, consistent with the notion that residual NdhC activity in respiratory-compromised cells remains targetable. Together, these findings provide insights into the molecular targeting of NdhC by CT and support the concept that the metabolic vulnerability of SCVs may be exploitable for the treatment of refractory S. aureus infections.
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