Arietis Pharma, Boston, Massachusetts, USA.
Arietis Pharma, Boston, Massachusetts, USA
Antimicrob Agents Chemother. 2019 Dec 20;64(1). doi: 10.1128/AAC.01554-19.
It is often difficult to cure endocarditis, osteomyelitis, and device-associated infections caused by Gram-positive pathogens, despite therapy with clinically appropriate antibiotics. This may be due to antibiotic tolerance or resistance development. Acyldepsipeptides (ADEPs) are a class of bactericidal compounds active against a variety of clinically important Gram-positive bacteria, including staphylococci, streptococci, and enterococci. ADEPs activate caseinolytic protease P (ClpP), killing high-density, nondividing cultures of bacteria that are tolerant to approved classes of antibiotics. Acyldepsipeptide analog 4 (ADEP4) was active against a panel of drug-resistant Gram-positive pathogens in MIC assays, with no preexisting resistance detected. Killing of stationary-phase cultures was observed when ADEP4 was combined with multiple classes of approved antibiotics. Additionally, a hollow-fiber infection model was used to assess the effects of ADEP4 antibiotic combinations on bacterial killing and resistance development. These studies were performed on high-density cultures of methicillin-resistant (MRSA), methicillin-susceptible (MSSA), and vancomycin-resistant (VRE). None of the approved antibiotics linezolid, ampicillin, and oxacillin tested alone had bactericidal activity under these conditions. ADEP4 initially caused killing, but regrowth of the culture was apparent within 96 h due to resistance. Combinations of ADEP4 with linezolid or oxacillin caused substantially improved killing of MRSA or MSSA cultures, respectively, and no regrowth due to resistance was observed. The combination of ADEP4 and ampicillin eradicated cultures of VRE to the limit of detection within 52 h. These data suggest that combining ClpP activators with traditional antibiotics may be a good strategy to treat complicated Gram-positive infections.
尽管采用了临床合适的抗生素治疗，但治疗由革兰氏阳性病原体引起的心内膜炎、骨髓炎和器械相关感染往往仍然较为困难。这可能是由于抗生素耐药性或耐药性的发展。酰基辅酶 A 二肽酶 (ADEP) 是一类对多种临床重要革兰氏阳性细菌具有杀菌活性的化合物，包括葡萄球菌、链球菌和肠球菌。ADEP 激活组织蛋白酶 P (ClpP)，杀死对批准的抗生素类别具有耐药性的高密度、非分裂细菌培养物。酰基辅酶 A 二肽类似物 4 (ADEP4) 在 MIC 测定中对一系列耐药性革兰氏阳性病原体具有活性，未检测到预先存在的耐药性。当 ADEP4 与多种批准的抗生素类别联合使用时，观察到对静止期培养物的杀伤作用。此外，还使用中空纤维感染模型来评估 ADEP4 抗生素组合对细菌杀伤和耐药发展的影响。这些研究是在耐甲氧西林金黄色葡萄球菌 (MRSA)、甲氧西林敏感金黄色葡萄球菌 (MSSA) 和万古霉素耐药肠球菌 (VRE) 的高密度培养物上进行的。单独测试的所有批准抗生素利奈唑胺、氨苄西林和苯唑西林在这些条件下均无杀菌活性。ADEP4 最初导致杀伤，但由于耐药性，培养物在 96 小时内出现再生。ADEP4 与利奈唑胺或苯唑西林的组合分别导致 MRSA 或 MSSA 培养物的杀菌活性显著改善，并且没有观察到由于耐药性而导致的再生长。ADEP4 与氨苄西林的组合在 52 小时内将 VRE 培养物根除到检测极限以下。这些数据表明，将 ClpP 激活剂与传统抗生素联合使用可能是治疗复杂革兰氏阳性感染的一种很好的策略。
