Formulation of host-targeted therapeutics against bacterial infections.
Formulation of host-targeted therapeutics against bacterial infections.
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DOI：
10.1016/j.trsl.2020.03.009
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发表时间：
2020-06
期刊：
影响因子：
--
通讯作者：
Ainslie KM
中科院分区：
文献类型：
--
作者：
Varma DM;Zahid MSH;Bachelder EM;Ainslie KM
由于对大多数一线抗生素的耐药性不断增加，全球细菌感染的负担正在上升，使得这些药物对几种临床上重要的病原体无效。对于表现出突出的细胞内生命周期的革兰氏阴性细菌来说，抗生素进入细胞的运输有限，加剧了这个问题。此外，抗生素在感染组织中的生物利用度差，需要更高的剂量和更长的治疗方案来治疗耐药感染。尽管新兴的抗生素可以解决这些问题，但随着时间的推移，耐药性仍然可能出现。宿主与病原体相互作用的知识不断丰富，激发了针对宿主的疗法（HDT）的研究和开发。 HDT 针对对细菌发病机制至关重要的宿主细胞机制，可单独治疗细菌感染或作为传统抗生素的辅助治疗。与直接影响细菌的传统抗生素不同，大多数 HDT 通过增强细胞内源性抗菌活性发挥作用，因此不易出现因选择压力而引起的细菌耐受性。因此，HDT 对细胞内胞质或液泡细菌非常有效，而大多数传统抗生素无法根除这些细菌。然而，HDT 的体内治疗效果依赖于足够的生物利用度。基于颗粒的制剂展示了实现靶向药物递送、增强细胞摄取以及增加 HDT 宿主细胞中药物浓度的潜力。本综述选择了针对临床重要病原体的 HDT，确定了可以提高其治疗效果的配方策略，并为进一步开发针对细菌感染的 HDT 提供了见解。
The global burden of bacterial infections is rising due to increasing resistance to the majority of first-line antibiotics, rendering these drugs ineffective against several clinically important pathogens. Limited transport of antibiotics into cells compounds this problem for gram-negative bacteria that exhibit prominent intracellular lifecycles. Furthermore, poor bioavailability of antibiotics in infected tissues necessitates higher doses and longer treatment regimens to treat resistant infections. Although emerging antibiotics can combat these problems, resistance still may develop over time. Expanding knowledge of host-pathogen interactions has inspired research and development of host-directed therapies (HDTs). HDTs target host-cell machinery critical for bacterial pathogenesis to treat bacterial infections alone or as adjunctive treatment with traditional antibiotics. Unlike traditional antibiotics that directly affect bacteria, a majority of HDTs function by boosting the endogenous antimicrobial activity of cells and are consequently less prone to bacterial tolerance induced by selection pressure. Therefore, HDTs can be quite effective against intracellular cytosolic or vacuolar bacteria, which a majority of traditional antibiotics are unable to eradicate. However, in vivo therapeutic efficacy of HDTs is reliant on adequate bioavailability. Particle-based formulations demonstrate the potential to enable targeted drug delivery, enhance cellular uptake, and increase drug concentration in the host cell of HDTs. This review selected HDTs for clinically important pathogens, identifies formulation strategies that can improve their therapeutic efficacy and offers insights toward further development of HDTs for bacterial infections.
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影响因子：
4.9
作者：
Duong AD;Collier MA;Bachelder EM;Wyslouzil BE;Ainslie KM
通讯作者：
Ainslie KM
影响因子：
4.9
作者：
Chiu, Hao-Chieh;Kulp, Samuel K.;Chen, Ching-Shih
通讯作者：
Chen, Ching-Shih
影响因子：
--
作者：
Akbarzadeh A;Rezaei-Sadabady R;Davaran S;Joo SW;Zarghami N;Hanifehpour Y;Samiei M;Kouhi M;Nejati-Koshki K
通讯作者：
Nejati-Koshki K
影响因子：
4.9
作者：
Bachelder EM;Beaudette TT;Broaders KE;Fréchet JM;Albrecht MT;Mateczun AJ;Ainslie KM;Pesce JT;Keane-Myers AM
通讯作者：
Keane-Myers AM
影响因子：
7.4
作者：
Andorko JI;Jewell CM
通讯作者：
Jewell CM