Overcoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-12.
Overcoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-12.
复制标题
使用 AR-12 克服细胞内肠沙门氏菌鼠伤寒血清型中抗生素敏感性降低的问题。
DOI：
10.1093/femsle/fnab062
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发表时间：
2021
影响因子：
2.1
通讯作者：
Ainslie,KristyM
中科院分区：
文献类型：
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作者：
Zahid,MShamimHasan;Varma,DevikaM;Johnson,MonicaM;Landavazo,Antonio;Bachelder,EricM;Blough,BruceE;Ainslie,KristyM
宿主导向疗法（HDTs）可以增强传统抗生素的活性。AR-12是一种很有前途的HDT，可对抗包括鼠伤寒沙门氏菌在内的细胞内病原体，并已显示通过调节自噬和Akt激酶途径发挥作用。由于AR-12不抑制嗜热菌的生长，而仅与受感染的宿主细胞一起起作用，因此我们假设AR-12可以增强细胞内宿主环境中较不敏感菌株中抗生素的活性。我们发现，在不存在抗生素的情况下，鼠伤寒沙门氏菌在巨噬细胞中的重复传代导致其细胞内对链霉素（STR）的敏感性降低4倍，但对细菌对AR-12的敏感性没有影响。此外，当用AR-12和STR的组合疗法处理宿主传代菌株时，与STR单一疗法相比，细胞内细菌负荷显著降低。此外，用AR-12和STR或氨苄青霉素共同处理感染多药耐药鼠伤寒沙门氏菌的巨噬细胞显示出细胞内细菌的清除增强。药物组合对嗜热菌没有引起这种作用。总体而言，AR-12增强了细胞内环境中较难降解的鼠伤寒沙门氏菌的清除。
Host-directed therapies (HDTs) could enhance the activity of traditional antibiotics. AR-12 is a promising HDT against intracellular pathogens includingSalmonella entericaserovar Typhimurium, and has been shown to act through modulation of autophagy and the Akt kinase pathway. Since AR-12 does not inhibit the growth of planktonic bacteria but only works in conjunction with the infected host-cell, we hypothesized that AR-12 could enhance the activity of antibiotics in less-susceptible strains in the intracellular host environment. We found that repetitive passaging ofS.typhimuriumin macrophages in the absence of antibiotics led to a 4-fold reduction in their intracellular susceptibility to streptomycin (STR), but had no effect on the bacteria's sensitivity to AR-12. Moreover, when the host-passaged strains were treated with a combined therapy of AR-12 and STR, there was a significant reduction of intracellular bacterial burden compared to STR monotherapy. Additionally, co-treatment of macrophages infected with multi-drug resistantS.typhimuriumwith AR-12 and STR or ampicillin showed enhanced clearance of the intracellular bacteria. The drug combination did not elicit this effect on planktonic bacteria. Overall, AR-12 enhanced the clearance of less susceptibleS.typhimuriumin an intracellular environment.