Crotteau Ashley N, Hubble Veronica B, Marrujo Santiana A, Mattingly Anne E, Melander Roberta J, Melander Christian
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Antibiotics (Basel). 2023 Oct 25;12(11):1563. doi: 10.3390/antibiotics12111563.
In 2019, five million deaths associated with antimicrobial resistance were reported by The Centers for Disease Control and Prevention (CDC). , a Gram-negative bacterial pathogen, is among the list of urgent threats. Previously, we reported 2-aminoimidazole (2-AI) adjuvants that potentiate macrolide activity against . In this study, we identify several of these adjuvants that sensitize to aminoglycoside antibiotics. Lead compounds and lower the tobramycin (TOB) minimum inhibitory concentration (MIC) against the TOB-resistant strain AB5075 from 128 μg/mL to 2 μg/mL at 30 μM. In addition, the lead compounds lower the TOB MIC against the TOB-susceptible strain AB19606 from 4 μg/mL to 1 μg/mL and 0.5 μg/mL, respectively, at 30 μM and 15 μM. The evolution of resistance to TOB and in AB5075 revealed mutations in genes related to protein synthesis, the survival of bacteria under environmental stressors, bacteriophages, and proteins containing Ig-like domains.
2019年，美国疾病控制与预防中心（CDC）报告了500万例与抗菌药物耐药性相关的死亡病例。革兰氏阴性细菌病原体 就在迫切威胁名单之中。此前，我们报道了增强大环内酯类药物对 活性的2-氨基咪唑（2-AI）佐剂。在本研究中，我们鉴定出了几种使 对氨基糖苷类抗生素敏感的此类佐剂。先导化合物 和 在30 μM时可将对妥布霉素（TOB）耐药菌株AB5075的妥布霉素（TOB）最低抑菌浓度（MIC）从128 μg/mL降至2 μg/mL。此外，先导化合物在30 μM和15 μM时分别将对TOB敏感菌株AB19606的TOB MIC从4 μg/mL降至1 μg/mL和0.5 μg/mL。AB5075中对TOB和 的耐药性演变揭示了与蛋白质合成、细菌在环境应激源下的存活、噬菌体以及含有Ig样结构域的蛋白质相关的基因突变。
