Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
Centre for Biomedical Science Research, School of Health, Leeds Beckett University, Leeds LS1 3HE, U.K.
Essays Biochem. 2023 Sep 13;67(5):769-780. doi: 10.1042/EBC20220222.
Antimicrobial resistance (AMR) is a major global problem and threat to humanity. The search for new antibiotics is directed towards targeting of novel microbial systems and enzymes, as well as augmenting the activity of pre-existing antimicrobials. Sulphur-containing metabolites (e.g., auranofin and bacterial dithiolopyrrolones [e.g., holomycin]) and Zn2+-chelating ionophores (PBT2) have emerged as important antimicrobial classes. The sulphur-containing, non-ribosomal peptide gliotoxin, biosynthesised by Aspergillus fumigatus and other fungi exhibits potent antimicrobial activity, especially in the dithiol form (dithiol gliotoxin; DTG). Specifically, it has been revealed that deletion of the enzymes gliotoxin oxidoreductase GliT, bis-thiomethyltransferase GtmA or the transporter GliA dramatically sensitise A. fumigatus to gliotoxin presence. Indeed, the double deletion strain A. fumigatus ΔgliTΔgtmA is especially sensitive to gliotoxin-mediated growth inhibition, which can be reversed by Zn2+ presence. Moreover, DTG is a Zn2+ chelator which can eject zinc from enzymes and inhibit activity. Although multiple studies have demonstrated the potent antibacterial effect of gliotoxin, no mechanistic details are available. Interestingly, reduced holomycin can inhibit metallo-β-lactamases. Since holomycin and gliotoxin can chelate Zn2+, resulting in metalloenzyme inhibition, we propose that this metal-chelating characteristic of these metabolites requires immediate investigation to identify new antibacterial drug targets or to augment the activity of existing antimicrobials. Given that (i) gliotoxin has been shown in vitro to significantly enhance vancomycin activity against Staphylococcus aureus, and (ii) that it has been independently proposed as an ideal probe to dissect the central 'Integrator' role of Zn2+ in bacteria - we contend such studies are immediately undertaken to help address AMR.
抗微生物药物耐药性（AMR）是一个全球性的重大问题，也是对人类的威胁。寻找新的抗生素的方向是针对新型微生物系统和酶，以及增强现有抗菌药物的活性。含硫代谢物（例如金诺芬和细菌二硫吡咯酮[例如霍霉素]）和 Zn2+螯合离载体（PBT2）已成为重要的抗菌药物类别。含硫的非核糖体肽类化合物曲霉菌毒素，由烟曲霉和其他真菌生物合成，具有很强的抗菌活性，特别是在二硫形式（二硫曲霉菌毒素；DTG）。具体而言，已经揭示出，酶曲霉菌毒素氧化还原酶 GliT、双硫甲基转移酶 GtmA 或转运蛋白 GliA 的缺失会使烟曲霉对曲霉菌毒素的存在变得极为敏感。实际上，双缺失菌株烟曲霉ΔgliTΔgtmA 对曲霉菌毒素介导的生长抑制特别敏感，而 Zn2+的存在可以逆转这种抑制。此外，DTG 是一种 Zn2+螯合剂，可以从酶中排出锌并抑制其活性。尽管多项研究表明曲霉菌毒素具有很强的抗菌作用，但目前尚不清楚其具体的作用机制。有趣的是，还原型霍霉素可以抑制金属-β-内酰胺酶。由于霍霉素和曲霉菌毒素可以螯合 Zn2+，从而抑制金属酶的活性，我们提出这些代谢物的这种金属螯合特性需要立即进行研究，以确定新的抗菌药物靶标或增强现有抗菌药物的活性。鉴于（i）曲霉菌毒素在体外已被证明可显著增强万古霉素对金黄色葡萄球菌的活性，并且（ii）它已被独立提出作为剖析细菌中 Zn2+的核心“整合酶”作用的理想探针-我们认为应立即进行此类研究，以帮助解决 AMR 问题。
