The Staphylococcus aureus Methicillin Resistance Factor FmtA Is a d -Amino Esterase That Acts on Teichoic Acids

Abstract

The methicillin resistance factor encoded by fmtA is a core member of the Staphylococcus aureus cell wall stimulon, but its function has remained elusive for the past two decades. First identified as a factor that affects methicillin resistance in S. aureus strains, FmtA was later shown to interact with teichoic acids and to localize to the cell division septum. We have made a breakthrough in understanding FmtA function. We show that FmtA hydrolyzes the ester bond between d-Ala and the backbone of teichoic acids, which are polyglycerol-phosphate or polyribitol-phosphate polymers found in the S. aureus cell envelope. FmtA contains two conserved motifs found in serine active-site penicillin-binding proteins (PBPs) and β-lactamases. The conserved SXXK motif was found to be important for the d-amino esterase activity of FmtA. Moreover, we show that deletion of fmtA (ΔfmtA) led to higher levels of d-Ala in teichoic acids, and this effect was reversed by complementation of ΔfmtA with fmtA. The positive charge on d-Ala partially masks the negative charge of the polyol-phosphate backbone of teichoic acids; hence, a change in the d-Ala content will result in modulation of their charge. Cell division, biofilm formation, autolysis, and colonization are among the many processes in S. aureus affected by the d-Ala content and overall charge of the cell surface teichoic acids. The esterase activity of FmtA and the regulation of fmtA suggest that FmtA functions as a modulator of teichoic acid charge, thus FmtA may be involved in S. aureus cell division, biofilm formation, autolysis, and colonization.

Structural and Functional Dynamics of Staphylococcus aureus Biofilms and Biofilm Matrix Proteins on Different Clinical Materials

“…Our findings suggested that PS, G and PG could provoke protein-dependent antibiotic resistance, as the enzymes lysostaphin resistance protein A (LyrA) and methicillin resistance-associated FemA/B and FmtA [103][104][105] were detected in PS, PG and/or G biofilms already at the 18 h time point, implying that biofilms on other materials may be more susceptible to certain antibiotics. In our study, chemotolerance tests were executed with different antibiotics covering a broad spectrum of mechanisms of action: vancomycin (glycopeptide: inhibits cell wall synthesis by forming complexes with peptidoglycan precursors [106]), penicillin G (B-lactam: inhibits cell wall synthesis via preventing peptidoglycan polymerization [107]), doxycycline (tetracycline: inhibits protein synthesis by binding to the 30S subunit of the bacterial ribosome [108]) and levofloxacin (fluoroquinolone: inhibits bacterial DNA gyrase and topoisomerase IV in Gram-negative and Gram-positive bacteria, respectively, and blocking DNA replication [109]).…”

Salt-Induced Stress Stimulates a Lipoteichoic Acid-Specific Three-Component Glycosylation System in Staphylococcus aureus

“…Kiriukhin and others have demonstrated that high NaCl concentrations inhibit transacylation from D-alanyl-DltC to the C2-OH of GroP and stimulate hydrolytic cleavage of the D-alanyl thioester (23,71). Alternatively, a recently described TA D-Ala esterase FmtA could play a role in reducing the LTA D-alanylation content under certain conditions (72). The mechanism of dealanylation by KOH treatment is more straightforward, as D-Ala LTA ester linkages are extremely labile to base.…”

High‐throughput transposon sequencing highlights the cell wall as an important barrier for osmotic stress in methicillin resistant Staphylococcus aureus and underlines a tailored response to different osmotic stressors

“…Transcriptome data (Mäder et al, ) suggested that gene 957 is in an operon with lcpB (Figure b), which is one of three wall teichoic acid (WTA) ligases present in S. aureus (Chan, Frankel, Dengler, Schneewind, & Missiakas, ; Over et al, ; Schaefer, Matano, Qiao, Kahne, & Walker, ). fmtA is located upstream of 957 and has been proposed to code for an esterase that can remove D‐alanine modifications from teichoic acids (Rahman et al, ) and is involved in methicillin resistance (Berger‐Bächi, Barberis‐Maino, Strässle, & Kayser, ). Genes coding for a predicted acetyltransferase and atl coding for the major S. aureus autolysin are found immediately downstream of the 957 operon (Oshida et al, ).…”