Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Retain Activity against Multidrug-Resistant Pseudomonas aeruginosa In Vitro and In Vivo.
Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Retain Activity against Multidrug-Resistant Pseudomonas aeruginosa In Vitro and In Vivo.
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DOI：
10.1128/mbio.02411-20
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发表时间：
2021-01-12
期刊：
影响因子：
6.4
通讯作者：
Greenberg DE
中科院分区：
文献类型：
--
作者：
Moustafa DA;Wu AW;Zamora D;Daly SM;Sturge CR;Pybus C;Geller BL;Goldberg JB;Greenberg DE
许多革兰氏阴性细菌对多种（如果不是全部）现有抗生素的耐药性越来越强。多重耐药铜绿假单胞菌是各种临床环境中医疗保健相关感染的主要原因，危及免疫功能低下的患者或患有慢性感染的患者，例如囊性纤维化 (CF) 患者。目前临床上的大多数抗菌药物都是对现有抗生素类别的改良，由于耐药性的出现，被认为是短期解决方案。铜绿假单胞菌因其多种生活方式、对大多数抗生素类别产生耐药性的能力以及在表面和某些宿主（例如患有囊性纤维化 (CF) 的宿主）中形成坚固的生物膜的能力，对新抗菌药物的发现提出了重大挑战。可以通过反义方法实现治疗假单胞菌的精确抗生素方法，特别是通过使用肽缀合的磷酸二酰胺吗啉低聚物（PPMO）。在这里，我们证明，靶向 acpP（酰基载体蛋白）、lpxC（UDP-（3-O-酰基）-N-乙酰氨基葡萄糖脱乙酰酶）和 rpsJ（30S 核糖体蛋白 S10）的 PPMO 可抑制几种多重耐药临床铜绿假单胞菌分离株的体外生长，其水平相当于有效对抗敏感菌株的水平。单独或与妥布霉素或哌拉西林-他唑巴坦联合使用，铅 PPMO 可以减少已形成的假单胞菌生物膜。在急性肺炎模型中，单独使用先导 PPMO 或与妥布霉素联合给药可减少治疗小鼠 24 小时的肺部细菌负荷，并降低感染后长达 5 天的发病率。与传统抗生素相比，PPMO 可减少同一模型中广泛耐药铜绿假单胞菌的细菌负担，并带来更高的存活率。这些数据表明，单独使用先导 PPMO 或与临床相关抗生素联合使用是对抗铜绿假单胞菌感染的一种有前景的治疗方法。
Numerous Gram-negative bacteria are becoming increasingly resistant to multiple, if not all, classes of existing antibiotics. Multidrug-resistant Pseudomonas aeruginosa bacteria are a major cause of health care-associated infections in a variety of clinical settings, endangering patients who are immunocompromised or those who suffer from chronic infections, such as people with cystic fibrosis (CF). Most antimicrobials currently in the clinical pipeline are modifications of existing classes of antibiotics and are considered short-term solutions due to the emergence of resistance. Pseudomonas aeruginosa represents a major challenge for new antimicrobial drug discovery due to its versatile lifestyle, ability to develop resistance to most antibiotic classes, and capacity to form robust biofilms on surfaces and in certain hosts such as those living with cystic fibrosis (CF). A precision antibiotic approach to treating Pseudomonas could be achieved with an antisense method, specifically by using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs). Here, we demonstrate that PPMOs targeting acpP (acyl carrier protein), lpxC (UDP-(3-O-acyl)-N-acetylglucosamine deacetylase), and rpsJ (30S ribosomal protein S10) inhibited the in vitro growth of several multidrug-resistant clinical P. aeruginosa isolates at levels equivalent to those that were effective against sensitive strains. Lead PPMOs reduced established pseudomonal biofilms alone or in combination with tobramycin or piperacillin-tazobactam. Lead PPMO dosing alone or combined with tobramycin in an acute pneumonia model reduced lung bacterial burden in treated mice at 24 h and reduced morbidity up to 5 days postinfection. PPMOs reduced bacterial burden of extensively drug-resistant P. aeruginosa in the same model and resulted in superior survival compared to conventional antibiotics. These data suggest that lead PPMOs alone or in combination with clinically relevant antibiotics represent a promising therapeutic approach for combating P. aeruginosa infections.