Department of Pediatrics, Division of Pulmonary, Allergy and Immunology, Cystic Fibrosis, and Sleep, Emory University School of Medicine, Atlanta, Georgia, USA.
Emory+Children's Center for Cystic Fibrosis and Airway Disease Research, Emory University School of Medicine, Atlanta, Georgia, USA.
mBio. 2021 Jan 12;12(1):e02411-20. doi: 10.1128/mBio.02411-20.
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. 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 could be achieved with an antisense method, specifically by using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs). Here, we demonstrate that PPMOs targeting (acyl carrier protein), (UDP-(3--acyl)--acetylglucosamine deacetylase), and (30S ribosomal protein S10) inhibited the growth of several multidrug-resistant clinical 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 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 infections. Numerous Gram-negative bacteria are becoming increasingly resistant to multiple, if not all, classes of existing antibiotics. Multidrug-resistant 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). Herein, we utilize antisense molecules that target mRNA of genes essential to bacterial growth, preventing the formation of the target proteins, including , , and We demonstrate here that antisense molecules targeted to essential genes, alone or in combination with clinically relevant antibiotics, were effective in reducing biofilms and protected mice in a lethal model of acute pneumonia.
大多数目前处于临床研发阶段的抗菌药物都是现有抗生素类别的改良物，由于耐药性的出现，这些药物被认为是短期解决方案。铜绿假单胞菌对新抗菌药物的发现构成了重大挑战，因为它的生活方式多样，能够对大多数抗生素类别产生耐药性，并且能够在表面和某些宿主（如患有囊性纤维化 (CF) 的宿主）中形成坚固的生物膜。通过反义方法，特别是使用肽偶联的磷二酰胺吗啉寡聚物 (PPMO)，可以实现针对铜绿假单胞菌的精准抗生素治疗。在这里，我们证明针对酰基载体蛋白 (acyl carrier protein)、UDP-(3-O-酰基)-N-乙酰葡糖胺脱乙酰酶 (UDP-(3-O-acyl)-N-acetylglucosamine deacetylase) 和 30S 核糖体蛋白 S10 的 PPMO 抑制了几种多药耐药临床铜绿假单胞菌分离株的生长，其水平与对敏感株有效的水平相当。先导 PPMO 单独或与妥布霉素或哌拉西林-他唑巴坦联合使用可降低已建立的铜绿假单胞菌生物膜。在急性肺炎模型中，先导 PPMO 单独给药或与妥布霉素联合给药可降低治疗小鼠 24 小时时肺部细菌负荷，并在感染后 5 天内降低发病率。PPMO 降低了同种模型中广泛耐药铜绿假单胞菌的细菌负荷，并与传统抗生素相比，提高了存活率。这些数据表明，先导 PPMO 单独或与临床相关抗生素联合使用，代表了对抗铜绿假单胞菌感染的一种有前途的治疗方法。许多革兰氏阴性菌对多种甚至所有现有抗生素的耐药性越来越强。多药耐药铜绿假单胞菌是多种临床环境中与健康相关感染的主要原因，危及免疫功能低下或患有慢性感染（如囊性纤维化 (CF) 患者）的患者。在此，我们利用针对细菌生长所必需的基因的 mRNA 的反义分子，防止靶蛋白的形成，包括 、 、和 。我们在此证明，针对必需基因的反义分子，单独或与临床相关抗生素联合使用，可有效减少生物膜并保护小鼠免受急性肺炎致死模型的影响。
