RND Pump-Mediated Efflux of Amotosalen, a Compound Used in Pathogen Inactivation Technology to Enhance Safety of Blood Transfusion Products, May Compromise Its Gram-Negative Anti-Bacterial Activity.
RND Pump-Mediated Efflux of Amotosalen, a Compound Used in Pathogen Inactivation Technology to Enhance Safety of Blood Transfusion Products, May Compromise Its Gram-Negative Anti-Bacterial Activity.
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DOI：
10.1128/msphere.00673-22
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发表时间：
2023-04-20
期刊：
影响因子：
4.8
通讯作者：
Kirby JE
中科院分区：
文献类型：
--
作者：
Green AB;Chiaraviglio L;Truelson KA;Zulauf KE;Cui M;Zhang Z;Ware MP;Flegel WA;Haspel RL;Yu EW;Kirby JE
病原体灭活是提高输液产品安全性的策略。目前在美国批准的血液制品的唯一病原体减少技术利用了一种名为amotosalen的peptide化合物，结合UVA光来杀灭细菌，病毒和原生动物。peptides与细菌多药外排泵底物具有结构相似性。由于这些外排泵通常在多药耐药病原体中过表达，我们通过遗传、生物物理和分子建模分析，基于多药外排机制，测试了当代耐药病原体是否可能对氨托沙林和其他peptides显示耐药性。肠球菌目、鲍曼不动杆菌和铜绿假单胞菌的主要外排系统是三重耐药-增殖-细胞分裂（RND）系统，其跨越革兰氏阴性病原体的内膜和外膜，并将抗生素从细菌细胞质排出到细胞外空间。我们提供的证据表明，amotosalen是一个外排底物的E。coli AcrAB、鲍氏不动杆菌AdeABC和铜绿假单胞菌MexXY RND外排泵。此外，我们发现，这些菌种和其他菌种的当代革兰氏阴性细菌分离株的体外MIC接近并超过了批准的血小板和血浆灭活程序中使用的氨托沙林浓度。这些发现表明，应进一步研究其他安全有效的灭活方法，以确定其对当代多重耐药细菌病原体的能力可能存在的差距。病原体灭活是提高输血制品安全性的一种策略。我们确定的化合物，amotosalen，广泛用于病原体灭活，作为细菌多药外排底物。具体地说，实验表明氨托沙林是通过大肠杆菌中的主要外排泵从细菌中泵出的。大肠杆菌、鲍曼不动杆菌和铜绿假单胞菌。这种外排泵通常在多药耐药病原体中过表达。重要的是，当代多重耐药肠球菌目、鲍曼不动杆菌、铜绿假单胞菌、伯克霍尔德氏菌属、和嗜麦芽窄食单胞菌分离株接近或超过批准的血小板和血浆灭活程序中使用的氨托沙林浓度，这可能是外排泵活性的结果。虽然我们的实验和血液制品病原体灭活方法之间存在重要差异，但这些研究结果表明，应进一步研究安全有效的灭活方法，以确定其对当代多重耐药细菌病原体的能力可能存在的差距。
Pathogen inactivation is a strategy to improve the safety of transfusion products. The only pathogen reduction technology for blood products currently approved in the US utilizes a psoralen compound, called amotosalen, in combination with UVA light to inactivate bacteria, viruses, and protozoa. Psoralens have structural similarity to bacterial multidrug efflux pump substrates. As these efflux pumps are often overexpressed in multidrug-resistant pathogens, we tested whether contemporary drug-resistant pathogens might show resistance to amotosalen and other psoralens based on multidrug efflux mechanisms through genetic, biophysical, and molecular modeling analysis. The main efflux systems in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa are tripartite resistance-nodulation-cell division (RND) systems, which span the inner and outer membranes of Gram-negative pathogens, and expel antibiotics from the bacterial cytoplasm into the extracellular space. We provide evidence that amotosalen is an efflux substrate for the E. coli AcrAB, Acinetobacter baumannii AdeABC, and P. aeruginosa MexXY RND efflux pumps. Furthermore, we show that the MICs for contemporary Gram-negative bacterial isolates for these species and others in vitro approached and exceeded the concentration of amotosalen used in the approved platelet and plasma inactivation procedures. These findings suggest that otherwise safe and effective inactivation methods should be further studied to identify possible gaps in their ability to inactivate contemporary, multidrug-resistant bacterial pathogens. IMPORTANCE Pathogen inactivation is a strategy to enhance the safety of transfused blood products. We identify the compound, amotosalen, widely used for pathogen inactivation, as a bacterial multidrug efflux substrate. Specifically, experiments suggest that amotosalen is pumped out of bacteria by major efflux pumps in E. coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. Such efflux pumps are often overexpressed in multidrug-resistant pathogens. Importantly, the MICs for contemporary multidrug-resistant Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa, Burkholderia spp., and Stenotrophomonas maltophilia isolates approached or exceeded the amotosalen concentration used in approved platelet and plasma inactivation procedures, potentially as a result of efflux pump activity. Although there are important differences in methodology between our experiments and blood product pathogen inactivation, these findings suggest that otherwise safe and effective inactivation methods should be further studied to identify possible gaps in their ability to inactivate contemporary, multidrug-resistant bacterial pathogens.
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影响因子：
9.8
作者：
Ayhan DH;Tamer YT;Akbar M;Bailey SM;Wong M;Daly SM;Greenberg DE;Toprak E
通讯作者：
Toprak E
DOI：
10.1073/pnas.86.7.2172
发表时间：
1989-04-01
影响因子：
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4.9
作者：
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通讯作者：
Plésiat, P
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影响因子：
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作者：
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影响因子：
4.6
作者：
Argyraki A;Markvart M;Stavnsbjerg C;Kragh KN;Ou Y;Bjørndal L;Bjarnsholt T;Petersen PM
通讯作者：
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