Annunziato Giannamaria, Spadini Costanza, Marchetti Marialaura, Franko Nina, Pavone Marialaura, Iannarelli Mattia, Bruno Agostino, Pieroni Marco, Bettati Stefano, Cabassi Clotilde Silvia, Campanini Barbara, Costantino Gabriele
P4T Group, Food and Drug Department, University of Parma, 43124 Parma, Italy.
Operative Unit of Animals Infectious Diseases, Department of Veterinary Science, University of Parma, 43126 Parma, Italy.
Pharmaceuticals (Basel). 2022 Jun 20;15(6):766. doi: 10.3390/ph15060766.
Antibacterial adjuvants are of great significance, since they allow one to downscale the therapeutic dose of conventional antibiotics and reduce the insurgence of antibacterial resistance. Herein, we report that -acetylserine sulfhydrylase (OASS) inhibitors could be used as colistin adjuvants to treat infections caused by critical pathogens spreading worldwide, , serovar Typhimurium, and . Starting from a hit compound endowed with a nanomolar dissociation constant, we have rationally designed and synthesized a series of derivatives to be tested against Typhimurium OASS isoenzymes, StOASS-A and StOASS-B. All acidic derivatives have shown good activities in the nanomolar range against both OASS isoforms in vitro. Minimal Inhibitory Concentrations (MICs) were then evaluated, as well as compounds' toxicity. The compounds endowed with good activity in vitro and low cytotoxicity have been challenged as a potential colistin adjuvant against pathogenic bacteria in vitro and the fractional inhibitory concentration (FIC) index has been calculated to define additive or synergistic effects. Finally, the target engagement inside the Typhimurium cells was confirmed by using a mutant strain in which the OASS enzymes were inactivated. Our results provide a robust proof of principle supporting OASS as a potential nonessential antibacterial target to develop a new class of adjuvants.
抗菌佐剂具有重要意义，因为它们能够降低传统抗生素的治疗剂量，并减少抗菌耐药性的产生。在此，我们报告称，O-乙酰丝氨酸巯基酶（OASS）抑制剂可用作黏菌素佐剂，以治疗由在全球范围内传播的关键病原体引起的感染，如鼠伤寒沙门氏菌血清型和其他菌株。从一种具有纳摩尔解离常数的先导化合物出发，我们合理设计并合成了一系列衍生物，用于测试其对鼠伤寒沙门氏菌OASS同工酶StOASS-A和StOASS-B的活性。所有酸性衍生物在体外对两种OASS同工型均表现出纳摩尔范围内的良好活性。随后评估了最低抑菌浓度（MIC）以及化合物的毒性。对在体外具有良好活性和低细胞毒性的化合物进行了挑战，作为潜在的黏菌素佐剂用于体外对抗病原菌，并计算了分数抑菌浓度（FIC）指数以确定相加或协同作用。最后，通过使用OASS酶失活的突变菌株，证实了鼠伤寒沙门氏菌细胞内的靶点结合。我们的结果提供了有力的原理证明，支持将OASS作为开发新型佐剂的潜在非必需抗菌靶点。
