School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Department of Biology, Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3SZ, United Kingdom.
Proc Natl Acad Sci U S A. 2023 Oct 10;120(41):e2308029120. doi: 10.1073/pnas.2308029120. Epub 2023 Oct 5.
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 mutations conferring penicillin resistance. The importance of variation at the locus was confirmed in natural and clinical populations in an analysis of >7,200 genomes. The 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 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.
是一种主要的人类病原体，对青霉素等β-内酰胺类抗生素的耐药性不断上升，对全球公共卫生构成了重大威胁。青霉素结合蛋白（PBPs）的突变可导致高水平的青霉素耐药性，但其他尚未完全了解的遗传因素也很重要。在这里，我们结合严格控制的实验室实验和群体分析，确定了一种独立于 PBPs 修饰的新青霉素耐药途径。最初的实验室选择实验确定了高频突变赋予青霉素耐药性。在对超过 7200 个基因组的分析中，在自然和临床人群中， 位点的变异的重要性得到了证实。通过这些方法确定的 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。我们的研究结果揭示了 作为一种赋予低水平青霉素耐药性的进化门户，快速出现的功能丧失突变。这种相对简单的基因组变化使细胞能够在种群中持续存在，从而通过适应性进化途径获得进一步的遗传变化和高水平的青霉素耐药性。
