Pyrimidine Analogues as a New Class of Gram-Positive Antibiotics, Mainly Targeting Thymineless-Death Related Proteins.,ACS Infectious Diseases

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Pyrimidine Analogues as a New Class of Gram-Positive Antibiotics, Mainly Targeting Thymineless-Death Related Proteins.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2019-09-20 , DOI: 10.1021/acsinfecdis.9b00305
Chihiro Oe ₁ , Hironori Hayashi _{2,

3} , Kazushige Hirata ₂ , Kumi Kawaji ₄ , Fusako Hashima ₂ , Mina Sasano ₄ , Maaya Furuichi ₄ , Emiko Usui ₄ , Makoto Katsumi ₂ , Yasuhiko Suzuki ₅ , Chie Nakajima ₅ , Mitsuo Kaku _{1,

2,

3} , Eiichi N Kodama _{4,

6}

Affiliation

Multidrug-resistant (MDR) bacteria are widespread throughout the world and pose an increasingly serious threat to human and animal health. Besides implementing strict measures to prevent improper antibiotic use, it remains essential that novel antibiotics must be developed. These antibiotics need to exert their activity via mechanisms different from those employed by currently approved antibiotics. In this study, we used several 5-fluorouracil (5-FU) analogues as chemical probes and investigated the potential of these pyrimidine analogues as antibacterial agents. Several 5-FU derivatives exerted potent activity against strains of Gram-positive cocci (GPC) that are susceptible or resistant toward approved antibiotics, without showing cross-resistance. Furthermore, we have provided evidence that the pyrimidine analogues exerted anti-GPC activity via thymineless death by inhibition of thymidylate synthetase (ThyA) and/or inhibition of RNA synthesis. Interestingly, whole genome resequencing of in vitro-selected, pyrimidine analogue-resistant Staphylococcus aureus mutants indicated that S. aureus strains with pyrimidine-analogue resistance induced an amino acid (AA) substitution, deletion, and/or insertion into thymineless-death related proteins except for ThyA, or enhanced the ThyA transcription level. Thus, S. aureus may avoid altering the ThyA function by introducing an AA substitution, suggesting that the pyrimidine analogues, which directly bind to ThyA without phosphorylation, may be more effective and show a higher genetic barrier than the pyrimidines that depend on phosphorylation for activity. The findings of this study may assist in the future development of a novel class of antibiotics for combating MDR GPC, including methicillin-resistant S. aureus and vancomycin-resistant Enterococci.

中文翻译：

嘧啶类似物是一类新型的革兰氏阳性抗生素，主要针对无胸腺死亡相关蛋白。

耐多药（MDR）细菌遍布世界各地，对人类和动物健康构成越来越严重的威胁。除了执行严格的措施以防止不当使用抗生素外，必须开发新的抗生素仍然至关重要。这些抗生素需要通过与目前批准的抗生素不同的机制发挥其活性。在这项研究中，我们使用了几种5-氟尿嘧啶（5-FU）类似物作为化学探针，并研究了这些嘧啶类似物作为抗菌剂的潜力。几种5-FU衍生物对革兰氏阳性球菌（GPC）菌株发挥了有效的活性，这些菌株对批准的抗生素敏感或耐药，而没有表现出交叉耐药性。此外，我们提供的证据表明嘧啶类似物通过抑制胸苷酸合成酶（ThyA）和/或抑制RNA合成，通过无胸腺嘧啶死亡而发挥抗GPC活性。有趣的是，体外选择的嘧啶类似物抗性的全基因组重测序金黄色葡萄球菌突变体表明，具有嘧啶类似物抗性的金黄色葡萄球菌菌株诱导除ThyA以外的氨基酸（AA）取代，缺失和/或插入无胸腺死亡相关蛋白，或增强ThyA转录水平。因此，金黄色葡萄球菌可以通过引入AA取代而避免改变ThyA功能，这表明与不依赖磷酸化作用的嘧啶类似，直接结合ThyA而没有磷酸化的嘧啶类似物可能更有效并且显示出更高的遗传屏障。。这项研究的结果可能有助于未来开发一种新型的抗MDR GPC的抗生素，包括耐甲氧西林的金黄色葡萄球菌。和耐万古霉素的肠球菌。

更新日期：2019-09-20

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