Abstract
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.
| Original language | English |
|---|---|
| Article number | e2308029120 |
| Number of pages | 10 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 120 |
| Issue number | 41 |
| DOIs | |
| Publication status | Published - 10 Oct 2023 |
Bibliographical note
Funding Information:ACKNOWLEDGMENTS. We would like to thank the Fagan, Mesnage, Corrigan, and Foster labs at the University of Sheffield for helpful advice and discussions. A special thanks to Guangchun Bai for the generous gift of the Pde1 antibody. We would like to thank Trevor Winstanley and David Partridge at Sheffield Teaching Hospitals for the gift of clinical strains. Live cell microscopy was carried out at the WolfsonLight MicroscopyFacilityat Sheffield.Genome sequencingwasprovidedby MicrobesNG (http://www.microbesng.com).This work was supported by a Medical Research Council New Investigator Research Grant (Grant number: MR/S009280/1) awarded to A.K.F.; a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number: 104110/Z/14/A) and a Lister Institute Research Prize 2018 to R.M.C.; S.K.S.was supported by MRC grants MR/M501608/1 and MR/L015080/1.
Data, Materials, and Software Availability:
All study data are included in the article and/or supporting information.
Publisher Copyright:
Copyright © 2023 the Author(s).
