Identification of the PA1113 Gene Product as an ABC Transporter Involved in the Uptake of Carbenicillin in Pseudomonas aeruginosa PAO1.
Identification of the PA1113 Gene Product as an ABC Transporter Involved in the Uptake of Carbenicillin in Pseudomonas aeruginosa PAO1.
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DOI：
10.3390/antibiotics9090596
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发表时间：
2020-09-11
期刊：
影响因子：
--
通讯作者：
Lomri NE
中科院分区：
文献类型：
--
作者：
Hulen C;Racine PJ;Chevalier S;Feuilloley M;Lomri NE
铜绿假单胞菌对抗生素的耐药性是多因素的、复杂的。而外排泵，如MexAB-OprM已被认为占主导地位，在这里，我们表明，一种新的ATP结合盒（ABC）转运介导的羧苄青霉素从周质流入细胞质，远离其细胞壁的目标在铜绿假单胞菌耐药这种抗生素发挥了重要作用。用维拉帕米（一种真核细胞中ABC转运蛋白的抑制剂）治疗铜绿假单胞菌可增加其对羧苄青霉素的敏感性。使用与已知维拉帕米蛋白靶点的氨基酸序列同源性作为探针，我们确定PA 1113基因产物，ABC转运蛋白，介导羧苄青霉素摄取到细菌细胞质中。对接和药理学分析表明，维拉帕米和羧苄青霉素竞争PA 1113基因蛋白上的同一位点，解释了维拉帕米对羧苄青霉素摄取的抑制作用，并进一步表明PA 1113 ABC转运蛋白约占铜绿假单胞菌羧苄青霉素耐药性的30%。我们的研究结果表明，PA 1113基因产物通过将其转运远离其细胞壁靶点来帮助介导羧苄青霉素耐药性，并代表了一个有前途的新治疗靶点。
The resistance of Pseudomonas aeruginosa to antibiotics is multi factorial and complex. Whereas efflux pumps such as MexAB-OprM have been thought to predominate, here we show that a novel ATP Binding Cassette (ABC) transporter that mediates influx of carbenicillin from the periplasm to the cytoplasm and away from its cell wall target plays an important role in the resistance of P. aeruginosa to this antibiotic. Treatment of P. aeruginosa with verapamil, an inhibitor of ABC transporters in eukaryotic cells, increases its sensitivity to carbenicillin. Using amino acid sequence homology with known verapamil protein targets as a probe, we determined that the PA1113 gene product, an ABC transporter, mediates carbenicillin uptake into the bacterial cytoplasm. Docking and pharmacological analyses showed that verapamil and carbenicillin compete for the same site on the PA1113 gene protein, explaining the inhibitory effect of verapamil on carbenicillin uptake, and furthermore suggest that the PA1113 ABC transporter accounts for about 30% of P. aeruginosa carbenicillin resistance. Our findings demonstrate that the PA1113 gene product helps mediate carbenicillin resistance by transporting it away from its cell wall target and represents a promising new therapeutic target.
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影响因子：
5.2
作者：
Mahamoud, Abdallah;Chevalier, Jacqueline;Pages, Jean-Marie
通讯作者：
Pages, Jean-Marie
影响因子：
3.3
作者：
COHN, RC;RUDZIENSKI, L;PUTNAM, RW
通讯作者：
PUTNAM, RW
影响因子：
3.6
作者：
Mao, WM;Warren, MS;Lomovskaya, O
通讯作者：
Lomovskaya, O
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
4.1
作者：
Majiduddin, FK;Materon, IC;Palzkill, TG
通讯作者：
Palzkill, TG