White Kylie, Nicoletti Gina, Cornell Hugh
STEM College, RMIT University, Melbourne, VIC 3001, Australia.
Antibiotics (Basel). 2021 Oct 27;10(11):1310. doi: 10.3390/antibiotics10111310.
The activity profile of a protein tyrosine phosphatase (PTP) inhibitor and redox thiol oxidant, nitropropenyl benzodioxole (NPBD), was investigated across a broad range of bacterial species. In vitro assays assessed inhibitory and lethal activity patterns, the induction of drug variants on long term exposure, the inhibitory interactions of NPBD with antibiotics, and the effect of plasma proteins and redox thiols on activity. A literature review indicates the complexity of PTP and redox signaling and suggests likely metabolic targets. NPBD was broadly bactericidal to pathogens of the skin, respiratory, urogenital and intestinal tracts. It was effective against antibiotic resistant strains and slowly replicating and dormant cells. NPBD did not induce resistant or drug-tolerant phenotypes and showed low cross reactivity with antibiotics in synergy assays. Binding to plasma proteins indicated lowered in-vitro bioavailability and reduction of bactericidal activity in the presence of thiols confirmed the contribution of thiol oxidation and oxidative stress to lethality. This report presents a broad evaluation of the antibacterial effect of PTP inhibition and redox thiol oxidation, illustrates the functional diversity of bacterial PTPs and redox thiols, and supports their consideration as novel targets for antimicrobial drug development. NPBD is a dual mechanism agent with an activity profile which supports consideration of tyrosine phosphatases and bacterial antioxidant systems as promising targets for drug development.
研究了蛋白质酪氨酸磷酸酶（PTP）抑制剂和氧化还原硫醇氧化剂硝基丙烯基苯并二恶唑（NPBD）对多种细菌的活性特征。体外试验评估了抑制和致死活性模式、长期暴露时药物变体的诱导情况、NPBD与抗生素的抑制相互作用以及血浆蛋白和氧化还原硫醇对活性的影响。文献综述表明了PTP和氧化还原信号传导的复杂性，并提出了可能的代谢靶点。NPBD对皮肤、呼吸道、泌尿生殖道和肠道的病原体具有广泛的杀菌作用。它对耐药菌株以及缓慢复制和休眠的细胞有效。NPBD不会诱导耐药或耐受药物的表型，并且在协同试验中与抗生素的交叉反应性较低。与血浆蛋白的结合表明体外生物利用度降低，而在存在硫醇的情况下杀菌活性降低证实了硫醇氧化和氧化应激对致死性的作用。本报告对PTP抑制和氧化还原硫醇氧化的抗菌作用进行了广泛评估，阐明了细菌PTP和氧化还原硫醇的功能多样性，并支持将它们视为抗菌药物开发的新靶点。NPBD是一种具有双重作用机制的药物，其活性特征支持将酪氨酸磷酸酶和细菌抗氧化系统视为有前景的药物开发靶点。
