Zhang Yongzheng, Rosado-Lugo Jesus D, Datta Pratik, Sun Yangsheng, Cao Yanlu, Banerjee Anamika, Yuan Yi, Parhi Ajit K
TAXIS Pharmaceuticals, Inc., 9 Deer Park Drive, Suite J-15, Monmouth Junction, NJ 08852, USA.
Antibiotics (Basel). 2022 May 26;11(6):716. doi: 10.3390/antibiotics11060716.
Efflux pumps in Gram-negative bacteria such as Pseudomonas aeruginosa provide intrinsic antimicrobial resistance by facilitating the extrusion of a wide range of antimicrobials. Approaches for combating efflux-mediated multidrug resistance involve, in part, developing indirect antimicrobial agents capable of inhibiting efflux, thus rescuing the activity of antimicrobials previously rendered inactive by efflux. Herein, TXA09155 is presented as a novel efflux pump inhibitor (EPI) formed by conformationally constraining our previously reported EPI TXA01182. TXA09155 demonstrates strong potentiation in combination with multiple antibiotics with efflux liabilities against wild-type and multidrug-resistant (MDR) P. aeruginosa. At 6.25 µg/mL, TXA09155, showed ≥8-fold potentiation of levofloxacin, moxifloxacin, doxycycline, minocycline, cefpirome, chloramphenicol, and cotrimoxazole. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA09155. TXA09155 was determined to lower the frequency of resistance (FoR) to levofloxacin and enhance the killing kinetics of moxifloxacin. Most importantly, TXA09155 outperformed the levofloxacin-potentiation activity of EPIs TXA01182 and MC-04,124 against a CDC/FDA panel of MDR clinical isolates of P. aeruginosa. TXA09155 possesses favorable physiochemical and ADME properties that warrant its optimization and further development.
铜绿假单胞菌等革兰氏阴性菌中的外排泵通过促进多种抗菌药物的外排提供内在的抗菌抗性。对抗外排介导的多药耐药性的方法部分包括开发能够抑制外排的间接抗菌剂，从而恢复先前因外排而失活的抗菌药物的活性。在此，TXA09155是一种新型外排泵抑制剂（EPI），它是通过对我们先前报道的EPI TXA01182进行构象限制而形成的。TXA09155与多种对野生型和多药耐药（MDR）铜绿假单胞菌具有外排倾向的抗生素联合使用时表现出强大的增效作用。在6.25μg/mL时，TXA09155对左氧氟沙星、莫西沙星、多西环素、米诺环素、头孢匹罗、氯霉素和复方新诺明的增效倍数≥8倍。多项生物物理和遗传学研究排除了膜破坏的可能性，并支持外排抑制是TXA09155的作用机制（MOA）。已确定TXA09155可降低对左氧氟沙星的耐药频率（FoR）并增强莫西沙星的杀菌动力学。最重要的是，在针对美国疾病控制与预防中心/美国食品药品监督管理局的一组铜绿假单胞菌MDR临床分离株时，TXA09155的左氧氟沙星增效活性优于EPI TXA01182和MC-04,124。TXA09155具有良好的理化性质和药代动力学性质，值得对其进行优化和进一步开发。
