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. 2020 Nov 30;21(23):9135. doi: 10.3390/ijms21239135

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© 2020 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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Novel mechanism of lysostaphin resistance in ST72 isolate and its associated metabolic pathway. After screening all the possible genes and mutation(s) known for lysostaphin resistance, no existing mechanisms (genes, mutations) of lysostaphin resistance was found to be functioned in ST72. (A) The schematic diagram shows the fundamental reason of lysostaphin resistance in staphylococcal cells due to the modification of glycine residues of pentaglycine bridge to serine; (B) Serine hydroxymethyltransferase (SHMT) is an indispensable enzyme for the one-carbon metabolism of serine/glycine interconversion and is linked to folate/methionine cycle. Therefore, glyA/shmT gene was hypothesized to be involved in lysostaphin resistance. (C) The metabolic pathway showing the interdependence of folate/methionine cycle and the key role of shmT serine/glycine homeostasis. One-carbon metabolism is responsible for the transfer of methyl group to various substrate and cofactors in folate, methionine cycle, and transsulfuration pathways. Various enzymes are denoted in green font while the substrates are depicted in regular font. The abbreviation used in the pathway wherein enzymes are DHPS (Dihydropteroate synthase); DHFS (Dihydrofolate synthase); DHFR (Dihydrofolate reductase); SHMT (Serine hydroxymethyltransferase); GcvPHT (glycine cleavage system); MTHFR (Methylene tetrahydrofolate reductase); MS (Methionine synthase); MAT (Methionine adenosyltransferase); MTases (Methyl transferases); AHCY (S-adenosylhomocysteine hydrolase), and CBS (Cystathionine beta-synthase) and substrates are THF (Tetrahydrofolate); 5, 10 CH₂-THF (5, 10 methylene tetrahydrofolate); 5-CH₂-THF (5-methylene tetrahydrofolate); Met (Methionine); SAM (S-adenosyl methionine); SAH (S-adenosyl homocysteine), and HCY (Homocysteine). One-carbon metabolism is important in cellular homeostasis by maintaining cellular seine/glycine through folate cycle, methionine cycle (protein synthesis), DNA synthesis and repair, redox balance, and various methylation reactions.