MRSA is a staph infection that is resistant to most antibiotics used to treat it. Bruce Donald is a computer scientist at Duke University who is working with the University of Connecticut to develop new drugs to fight MRSA. The team discovered how a single small change in a drug's function can make a big difference.
They looked at dihydrofolate reductase, an antibiotic that is used to fight MRSA. Drugs that bind to MRSA have a specific three-dimensional structure that only allows them to attach to them, which is similar to locks and keys.
Drugs can lose their effectiveness if there is a change in the structure of a bacterium. The F98Y is a well-known resistance variation. Graham Holt, a graduate student in the Donald lab, said that the change in the 98th amino acid has a huge effect.
The OSPREY suite of programs was developed in the Donald lab and was thought to be able to predict thismutation. He could not. He went back to look at the starting structure to figure out why he couldn't predict the change.
Donald said that they looked at the data from the crystallographer and found something strange. In trying to determine the structure of the F98Y Mutant, crystallographers used a computer program that wasn't known to them and made a mirror image of the NADPH cofactor to get a better fit. The chemical species they discovered through their analysis are1-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-65561-6556
Donald said that they believe the flipped cofactor is due to the F98Y mutation.
The basis for resistance has been changed by thischiral evasion. Donald and his colleagues now know how a single small change in the lock changed the structure of the drug.
This is the first example of an enzyme that exploits the cofactor in order to evade its inhibitors.
The Donald lab showed that by taking flipped chirality into account, OSPREY's predictions closely match experimental measurements of inhibitor potency. The University of Connecticut conducted biochemical experiments to test the theory and provide structural evidence.
Donald said that the discovery of chiral evasion should lead to better drug designs.
More information: Siyu Wang et al, Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus, PLOS Computational Biology (2022). DOI: 10.1371/journal.pcbi.1009855 Journal information: PLoS Computational Biology Citation: How superbugs use mirror images to create antibiotic resistance (2022, February 17) retrieved 18 February 2022 from https://phys.org/news/2022-02-superbugs-mirror-images-antibiotic-resistance.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
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