Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.
Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.
复制标题
DOI：
10.1371/journal.pone.0069646
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zechiedrich L
中科院分区：
文献类型：
--
作者：
Carlson-Banning KM;Chou A;Liu Z;Hamill RJ;Song Y;Zechiedrich L
由革兰氏阴性细菌引起的抗生素耐药性感染是一个主要的医疗保健问题。重新使用药物可以避免与开发对抗这些耐药性感染所需的新抗菌剂相关的时间和金钱限制。在这里，我们确定了专利过期的抗真菌剂，环吡酮，作为一个候选人，重新用途的抗生素使用。为了测试环吡酮对耐药病原体的疗效，我们使用了鲍曼不动杆菌、大肠埃希菌和肺炎克雷伯菌临床分离株的精心收集，这些临床分离株代表已知的抗生素耐药表型。我们发现，无论抗生素耐药性如何，5-15 μg/ml浓度的环吡酮都能抑制细菌生长。在这些相同的浓度下，环吡酮减少了铜绿假单胞菌临床分离株的生长，但这些病原体中的一些需要更高的环吡酮浓度才能完全阻断生长。为了确定环吡酮如何抑制细菌生长，我们在大肠杆菌中进行了过表达筛选。杆菌该筛选显示，编码UDP-葡萄糖4-差向异构酶的galE在其他限制性环吡酮浓度下拯救了细菌生长。我们发现环吡酮不抑制纯化的E.而ΔgalU、ΔgalE、ΔrfaI或ΔrfaB突变株的环吡酮最低抑菌浓度均低于亲本菌株。galU、galE、rfaI和rfaB基因都编码利用UDP-半乳糖或UDP-葡萄糖进行半乳糖代谢和脂多糖（LPS）生物合成的酶。事实上，我们发现环吡酮改变了E.大肠杆菌临床分离株。综上所述，我们的数据表明，环吡酮影响半乳糖代谢和LPS生物合成，这两个途径对细菌生长和毒力很重要。在临床使用超过20年中，缺乏对环吡酮的任何真菌耐药性的报道，其优异的安全性特征、新的靶标和功效，使得环吡酮成为用于对抗多药耐药性问题革兰氏阴性病原体的有希望的潜在抗微生物剂。
Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that ciclopirox, at 5–15 µg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher ciclopirox concentrations to completely block growth. To determine how ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive ciclopirox concentrations. We found that ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, ΔgalU, ΔgalE, ΔrfaI, or ΔrfaB mutant strains all have lower ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactose metabolism and lipopolysaccharide (LPS) biosynthesis. Indeed, we found that ciclopirox altered LPS composition of an E. coli clinical isolate. Taken together, our data demonstrate that ciclopirox affects galactose metabolism and LPS biosynthesis, two pathways important for bacterial growth and virulence. The lack of any reported fungal resistance to ciclopirox in over twenty years of use in the clinic, its excellent safety profiles, novel target(s), and efficacy, make ciclopirox a promising potential antimicrobial agent to use against multidrug-resistant problematic gram-negative pathogens.
登录
查看更多内容
DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
4.9
作者：
Boyd, Lauren Becnel;Maynard, Merry J.;Zechiedrich, Lynn
通讯作者：
Zechiedrich, Lynn
DOI：
10.1111/j.1432-1033.1995.607_2.x
发表时间：
1995-10-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BROCKHAUSEN, I;YANG, JM;TAYLORPAPADIMITRIOU, J
通讯作者：
TAYLORPAPADIMITRIOU, J
影响因子：
14.9
作者：
Cole JR;Wang Q;Cardenas E;Fish J;Chai B;Farris RJ;Kulam-Syed-Mohideen AS;McGarrell DM;Marsh T;Garrity GM;Tiedje JM
通讯作者：
Tiedje JM
影响因子：
11.8
作者：
Boucher, Helen W.;Talbot, George H.;Bartlett, John
通讯作者：
Bartlett, John