Loss of Pde1 function acts as an evolutionary gateway to penicillin resistance in Streptococcus pneumoniae.
Loss of Pde1 function acts as an evolutionary gateway to penicillin resistance in Streptococcus pneumoniae.
复制标题
PDE1功能的丧失充当肺炎链球菌中青霉素耐药性的进化门户。
DOI：
10.1073/pnas.2308029120
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发表时间：
2023-10-10
影响因子：
11.1
通讯作者：
Fenton, Andrew K.
中科院分区：
文献类型：
--
作者：
Kobras, Carolin M.;Monteith, William;Somerville, Sophie;Delaney, James M.;Khan, Imran;Brimble, Camilla;Corrigan, Rebecca M.;Sheppard, Samuel K.;Fenton, Andrew K.
关键词：
肺炎链球菌是一种重要的细菌病原体，导致全世界许多严重感染。感染通常用青霉素抗生素治疗。随着时间的推移，这为耐药菌株的出现提供了选择压力，减少了治疗选择并威胁到患者。结合实验室进化和比较基因组学方法，我们发现了 Pde1 酶中独特的功能丧失突变，这些突变在缺乏经典耐药决定因素的情况下导致青霉素耐药。我们在临床分离株中证实了这种效应，并描述了自然遗传变异对 Pde1 功能的影响。迄今为止，终末期青霉素抗性基因的表征尚未带来有效的缓解。在这里，通过描述导致耐药性的进化事件，我们为针对耐药性肺炎链球菌的干预提供了不同的可能性。肺炎链球菌是主要的人类病原体，对青霉素等β-内酰胺抗生素的耐药性不断上升，对全球公共卫生构成重大威胁。青霉素结合蛋白（PBP）中发生的突变可以赋予高水平的青霉素耐药性，但其他知之甚少的遗传因素也很重要。在这里，我们结合了严格控制的实验室实验和群体分析，以确定独立于 PBP 修饰的新青霉素耐药途径。最初的实验室选择实验确定了导致肺炎链球菌青霉素耐药性的高频 pde1 突变。对超过 7,200 个肺炎链球菌基因组的分析在自然和临床人群中证实了 pde1 基因座变异的重要性。通过这些方法鉴定的 pde1 突变降低了细菌细胞中 Pde1 酶的水解活性，从而提高了环二腺苷单磷酸和青霉素耐药性的水平。我们的结果揭示了 pde1 功能突变的快速从头丧失，作为赋予低水平青霉素耐药性的进化途径。这种相对简单的基因组变化使细胞能够在适应性进化途径中持续存在于群体中，以获得进一步的遗传变化和高水平的青霉素耐药性。
Streptococcus pneumoniae is an important bacterial pathogen responsible for many serious infections worldwide. Infections are often treated with penicillin antibiotics. This provides a selection pressure for the emergence of resistant strains over time, reducing treatment options and threatening patients. Combining lab evolutionary and comparative genomics approaches, we identify unique loss of function mutations in the Pde1 enzyme that lead to penicillin resistance in the absence of classical resistance determinants. We confirm this effect across clinical isolates and characterize the impact of natural genetic variation on Pde1 function. Characterization of end-stage penicillin resistance genes has, so far, not led to effective mitigations. Here, by characterizing the evolutionary events leading toward resistance, we open different possibilities for interventions against resistant S. pneumoniae. Streptococcus pneumoniae is a major human pathogen and rising resistance to β-lactam antibiotics, such as penicillin, is a significant threat to global public health. Mutations occurring in the penicillin-binding proteins (PBPs) can confer high-level penicillin resistance but other poorly understood genetic factors are also important. Here, we combined strictly controlled laboratory experiments and population analyses to identify a new penicillin resistance pathway that is independent of PBP modification. Initial laboratory selection experiments identified high-frequency pde1 mutations conferring S. pneumoniae penicillin resistance. The importance of variation at the pde1 locus was confirmed in natural and clinical populations in an analysis of >7,200 S. pneumoniae genomes. The pde1 mutations identified by these approaches reduce the hydrolytic activity of the Pde1 enzyme in bacterial cells and thereby elevate levels of cyclic-di-adenosine monophosphate and penicillin resistance. Our results reveal rapid de novo loss of function mutations in pde1 as an evolutionary gateway conferring low-level penicillin resistance. This relatively simple genomic change allows cells to persist in populations on an adaptive evolutionary pathway to acquire further genetic changes and high-level penicillin resistance.
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