Institute for Infection Medicine, Christian-Albrechts-University of Kiel, Brunswiker Str. 4, 24105, Kiel, Germany.
Infection. 2021 Aug;49(4):569-589. doi: 10.1007/s15010-020-01547-9. Epub 2020 Dec 15.
Advances in structural biology, genetics, bioinformatics, etc. resulted in the availability of an enormous pool of information enabling the analysis of the ancestry of pro- and eukaryotic genes and proteins.
This review summarizes findings of structural and/or functional homologies of pro- and eukaryotic enzymes catalysing analogous biological reactions because of their highly conserved active centres so that non-antibiotics interacted with bacterial targets.
Protease inhibitors such as staurosporine or camostat inhibited bacterial serine/threonine or serine/tyrosine protein kinases, serine/threonine phosphatases, and serine/threonine kinases, to which penicillin-binding-proteins are linked, so that these drugs synergized with β-lactams, reverted aminoglycoside-resistance and attenuated bacterial virulence. Calcium antagonists such as nitrendipine or verapamil blocked not only prokaryotic ion channels but interacted with negatively charged bacterial cell membranes thus disrupting membrane energetics and inducing membrane stress response resulting in inhibition of P-glycoprotein such as bacterial pumps thus improving anti-mycobacterial activities of rifampicin, tetracycline, fluoroquinolones, bedaquilin and imipenem-activity against Acinetobacter spp. Ciclosporine and tacrolimus attenuated bacterial virulence. ACE-inhibitors like captopril interacted with metallo-β-lactamases thus reverting carbapenem-resistance; prokaryotic carbonic anhydrases were inhibited as well resulting in growth impairment. In general, non-antibiotics exerted weak antibacterial activities on their own but synergized with antibiotics, and/or reverted resistance and/or attenuated virulence.
Data summarized in this review support the theory that prokaryotic proteins represent targets for non-antibiotics because of a common evolutionary origin of bacterial- and mammalian targets resulting in highly conserved active centres of both, pro- and eukaryotic proteins with which the non-antibiotics interact and exert antibacterial actions.
结构生物学、遗传学、生物信息学等方面的进展，产生了大量的信息，使人们能够分析原核生物和真核生物基因和蛋白质的起源。
本文综述了结构和/或功能同源性的发现，原核生物和真核生物的酶催化类似的生物反应，因为它们高度保守的活性中心，使非抗生素与细菌靶标相互作用。
蛋白酶抑制剂，如星孢菌素或卡莫司他，抑制细菌丝氨酸/苏氨酸或丝氨酸/酪氨酸蛋白激酶、丝氨酸/苏氨酸磷酸酶和丝氨酸/苏氨酸激酶，与青霉素结合蛋白相连，因此这些药物与β-内酰胺类药物协同作用，逆转氨基糖苷类耐药性，并减弱细菌毒力。钙拮抗剂，如尼群地平或维拉帕米，不仅阻断原核离子通道，还与带负电荷的细菌细胞膜相互作用，从而破坏膜能量学，并诱导膜应激反应，导致 P-糖蛋白如细菌泵的抑制，从而提高利福平、四环素、氟喹诺酮、贝达喹啉和亚胺培南对分枝杆菌的活性，对抗不动杆菌属。环孢素和他克莫司减弱细菌毒力。血管紧张素转换酶抑制剂，如卡托普利，与金属-β-内酰胺酶相互作用，从而逆转碳青霉烯类耐药性；原核碳酸酐酶也被抑制，导致生长受损。一般来说，非抗生素本身具有较弱的抗菌活性，但与抗生素协同作用，和/或逆转耐药性和/或减弱毒力。
本文综述的数据支持这样一种理论，即原核蛋白是抗生素的非抗生素的靶点，因为细菌和哺乳动物靶标具有共同的进化起源，导致原核生物和真核生物蛋白质的高度保守的活性中心，非抗生素与这些蛋白质相互作用并发挥抗菌作用。
