A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans.
A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans.
复制标题
化学筛选鉴定出具有对抗真菌病原体白色念珠菌活性的结构多样的金属螯合剂。
DOI：
10.1128/spectrum.04095-23
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发表时间：
2024
影响因子：
3.7
通讯作者：
Cowen,LeahE
中科院分区：
文献类型：
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作者：
Fallah,Sara;Duncan,Dustin;Reichl,KyleD;Smith,MichaelJ;Wang,Wenyu;PorcoJr,JohnA;Brown,LaurenE;Whitesell,Luke;Robbins,Nicole;Cowen,LeahE
白色念珠菌是人类最常见的真菌病原体之一，可引起从浅表感染到致命的全身性真菌病的多种疾病。目前，只有三种主要的抗真菌药物可用于治疗全身感染：唑类，多烯类和棘白菌素类。令人担忧的是，这些抗真菌药对C.白念珠菌病的进展受到对药物的基础耐受性和耐药机制的发展的阻碍，如药物靶点的改变、应激反应的调节和外排泵的过度表达。因此，迫切需要确定新的抗真菌策略。为了应对这一挑战，我们从波士顿大学分子发现中心（BU-CMD）化学文库中筛选了3，049种结构多样的化合物。albicans临床分离株，鉴定出17个抑制C.白念珠菌生长>80%。其中最有效的化合物是CMLD 013360、CMLD 012661和CMLD 012693，这些分子代表了两种不同的化学支架，包括3-羟基喹啉酮和氧杂蒽酮天然产物。基于结构分析，假设CMLD 013360、CMLD 012661和CMLD 012693通过金属螯合作用发挥抗真菌活性。后续研究表明，所有三种化合物都对非白色念珠菌（包括耳念珠菌和光滑念珠菌）具有抗真菌活性，其中氧杂蒽酮天然产物CMLD 013360还对致病性霉菌烟曲霉（Aspergillus fumigatus）具有活性。培养基中补充金属营养素，即三价铁或二价铁，挽救C。albicans生长，证实这些化合物作为金属螯合剂。因此，这项工作确定和表征两种化学支架螯合铁，以抑制临床相关的真菌病原体的生长。白色念珠菌重要性侵袭性真菌感染的全球发病率正在以惊人的速度增长。由机会致病菌白色念珠菌引起的系统性念珠菌病是危及生命的真菌感染的最常见原因。然而，由于有限的抗真菌药物种类和抗真菌药物耐药性的上升，迫切需要确定新的治疗方法。通过筛选来自波士顿大学分子发现中心（BU-CMD）的化合物集合，我们确定了三种化合物，代表了两种不同的化学支架，显示出对C的活性。白色念珠菌后续分析证实，这些分子也对其他致病真菌包括念珠菌和烟曲霉有活性。最后，我们确定这些化合物抑制C.通过铁螯合作用进行白念珠菌培养。总的来说，这项观察描述了两种新型化学支架，对不同的真菌病原体具有抗真菌活性。
Candida albicans, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals againstC. albicansis hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug’s target, modulation of stress responses, and overexpression of efflux pumps. Thus, the need to identify novel antifungal strategies is dire. To address this challenge, we screened 3,049 structurally-diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library against aC. albicansclinical isolate and identified 17 molecules that inhibitedC. albicansgrowth by >80% relative to controls. Among the most potent compounds were CMLD013360, CMLD012661, and CMLD012693, molecules representing two distinct chemical scaffolds, including 3-hydroxyquinolinones and a xanthone natural product. Based on structural insights, CMLD013360, CMLD012661, and CMLD012693 were hypothesized to exert antifungal activity through metal chelation. Follow-up investigations revealed all three compounds exerted antifungal activity against non-albicansCandida, includingCandida aurisandCandida glabrata, with the xanthone natural product CMLD013360 also displaying activity against the pathogenic mouldAspergillus fumigatus. Media supplementation with metallonutrients, namely ferric or ferrous iron, rescuedC. albicansgrowth, confirming these compounds act as metal chelators. Thus, this work identifies and characterizes two chemical scaffolds that chelate iron to inhibit the growth of the clinically relevant fungal pathogenC. albicansIMPORTANCEThe worldwide incidence of invasive fungal infections is increasing at an alarming rate. Systemic candidiasis caused by the opportunistic pathogenCandida albicansis the most common cause of life-threatening fungal infection. However, due to the limited number of antifungal drug classes available and the rise of antifungal resistance, an urgent need exists for the identification of novel treatments. By screening a compound collection from the Boston University Center for Molecular Discovery (BU-CMD), we identified three compounds representing two distinct chemical scaffolds that displayed activity againstC. albicans. Follow-up analyses confirmed these molecules were also active against other pathogenic fungal species includingCandida aurisandAspergillus fumigatus. Finally, we determined that these compounds inhibit the growth ofC. albicansin culture through iron chelation. Overall, this observation describes two novel chemical scaffolds with antifungal activity against diverse fungal pathogens.