Center for Microbial Dynamics & Infection, School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA.
Center for Microbial Dynamics & Infection, School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA
mBio. 2021 May 4;12(3):e00458-21. doi: 10.1128/mBio.00458-21.
Bacteriocins are proteinaceous antimicrobials produced by bacteria that are active against other strains of the same species. R-type pyocins are phage tail-like bacteriocins produced by Due to their antipseudomonal activity, R-pyocins have potential as therapeutics in infection. is a Gram-negative opportunistic pathogen and is particularly problematic for individuals with cystic fibrosis (CF). organisms from CF lung infections develop increasing resistance to antibiotics, making new treatment approaches essential. populations become phenotypically and genotypically diverse during infection; however, little is known of the efficacy of R-pyocins against heterogeneous populations. R-pyocins vary by subtype (R1 to R5), distinguished by binding to different residues on the lipopolysaccharide (LPS). Each type varies in killing spectrum, and each strain produces only one R-type. To evaluate the prevalence of different R-types, we screened strains from the International Pseudomonas Consortium Database (IPCD) and from our biobank of CF strains. We found that (i) R1-types were the most prevalent R-type among strains from respiratory sources, (ii) a large number of strains lack R-pyocin genes, and (iii) isolates collected from the same patient have the same R-type. We then assessed the impact of intrastrain diversity on R-pyocin susceptibility and found a heterogenous response to R-pyocins within populations, likely due to differences in the LPS core. Our work reveals that heterogeneous populations of microbes exhibit variable susceptibility to R-pyocins and highlights that there is likely heterogeneity in response to other types of LPS-binding antimicrobials, including phage. R-pyocins have potential as alternative therapeutics against in chronic infection; however, little is known about the efficacy of R-pyocins in heterogeneous bacterial populations. is known to become resistant to multiple antibiotics and to evolve phenotypic and genotypic diversity over time; thus, it is particularly difficult to eradicate in chronic cystic fibrosis (CF) lung infections. In this study, we found that populations from CF lungs maintain the same R-pyocin genotype but exhibit heterogeneity in susceptibility to R-pyocins from other strains. Our findings suggest there is heterogeneity in response to other types of LPS-binding antimicrobials, such as phage, highlighting the necessity of further studying the potential of LPS-binding antimicrobial particles as alternative therapies in chronic infections.
细菌素是由细菌产生的具有抗菌活性的蛋白质，可针对同种菌株的其他菌株发挥作用。R 型噬菌体尾状细菌素是由噬菌体产生的细菌素。由于其抗假单胞菌活性，R 型噬菌体尾状细菌素有作为感染治疗药物的潜力。铜绿假单胞菌是一种革兰氏阴性机会性病原体，对囊性纤维化 (CF) 患者尤其成问题。来自 CF 肺部感染的铜绿假单胞菌对抗生素的耐药性不断增加，因此需要新的治疗方法。在感染过程中，铜绿假单胞菌种群在表型和基因型上变得多样化；然而，对于 R 型噬菌体尾状细菌素对异质种群的疗效知之甚少。R 型噬菌体尾状细菌素根据亚型（R1 到 R5）而有所不同，其区别在于与脂多糖 (LPS) 上的不同残基结合。每种类型的杀伤谱不同，每种菌株仅产生一种 R 型。为了评估不同 R 型的流行程度，我们筛选了国际铜绿假单胞菌联合会数据库 (IPCD) 和我们的 CF 菌株生物库中的菌株。我们发现：(i) R1 型是呼吸道来源菌株中最常见的 R 型；(ii) 大量菌株缺乏 R 型噬菌体尾状细菌素基因；(iii) 来自同一患者的分离株具有相同的 R 型。然后，我们评估了菌株内多样性对 R 型噬菌体尾状细菌素敏感性的影响，发现种群内对 R 型噬菌体尾状细菌素有异质反应，这可能是由于 LPS 核心的差异所致。我们的工作表明，微生物的异质种群对 R 型噬菌体尾状细菌素有不同的敏感性，并强调对于其他类型的 LPS 结合抗菌剂，包括噬菌体，可能存在反应的异质性。R 型噬菌体尾状细菌素有作为慢性感染中铜绿假单胞菌的替代治疗剂的潜力；然而，对于 R 型噬菌体尾状细菌素在异质细菌种群中的疗效知之甚少。铜绿假单胞菌已知会对多种抗生素产生耐药性，并随着时间的推移表现出表型和基因型的多样性；因此，在慢性囊性纤维化 (CF) 肺部感染中特别难以根除。在这项研究中，我们发现 CF 肺部的铜绿假单胞菌种群保持相同的 R 型噬菌体尾状细菌素基因型，但对来自其他菌株的 R 型噬菌体尾状细菌素有异质性敏感性。我们的研究结果表明，对于其他类型的 LPS 结合抗菌剂（如噬菌体），存在反应的异质性，这突出表明需要进一步研究 LPS 结合抗菌颗粒作为慢性感染替代疗法的潜力。
