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. 2019 Oct 9;20(20):4996. doi: 10.3390/ijms20204996

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© 2019 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Resistance mechanisms against antifolates. Stars indicate possible mutations associated with the appearance of resistance against antifolates. Some mechanisms apply to eukaryotic cells too. Each number indicates the resistance mechanism described in the text: 1. Mutations affecting the genes that code the antifolates-targeted enzymes; 2. Emergence of novel resistant isoforms of the antifolates-targeted enzymes; 3. Reduction in cell permeability and increase in efflux proteins; 4. Overexpression of target enzymes; 5. Deregulation of polyglutamation; and 6. Thymine auxotrophy.