9.B.415. The Putative Transporter Auxiliary Factor AuxB (AuxB) Family A major determinant of beta-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) is the drug insensitive transpeptidase, PBP2a, encoded by mecA. However, full expression of the resistance phenotype requires auxiliary factors. Mikkelsen et al. 2021 identified two such factors, auxiliary factor A (AuxA, SAUSA300_0980) and B (AuxB, SAUSA300_1003) in a screen against mutants with increased susceptibility to beta-lactams in the MRSA strain JE2. auxA and auxB encode transmembrane proteins, with AuxA predicted to be a transporter with 10 or 11 TMSs. Inactivation of auxA or auxB enhanced beta-lactam susceptibility in community-, hospital- and livestock associated MRSA strains without affecting PBP2a expression, peptidoglycan cross-linking or wall teichoic acid synthesis. Both mutants displayed increased susceptibility to inhibitors of lipoteichoic acid (LTA) synthesis and alanylation pathways, and released LTA even in the absence of beta-lactams. The beta-lactam susceptibility of the aux mutants was suppressed by mutations inactivating gdpP, which was previously found to allow growth of mutants lacking the lipoteichoic synthase enzyme, LtaS. Using the Galleria mellonella infection model, Mikkelsen et al. 2021 observed enhanced survival of larvae inoculated with either auxA or auxB mutants compared to the wild type strain following treatment with amoxicillin. Thus, AuxA and AuxB are central for LTA stability and potential inhibitors can be used to re-sensitize MRSA strains to beta-lactams and combat MRSA infections.
References:
Mikkelsen, K., W. Sirisarn, O. Alharbi, M. Alharbi, H. Liu, K. Nøhr-Meldgaard, K. Mayer, M. Vestergaard, L.A. Gallagher, J.P. Derrick, A.J. McBain, J. Biboy, W. Vollmer, J.P. O''Gara, T. Grunert, H. Ingmer, and G. Xia. (2021). The Novel Membrane-Associated Auxiliary Factors AuxA and AuxB Modulate β-lactam Resistance in MRSA by stabilizing Lipoteichoic Acids. Int J Antimicrob Agents 106283. [Epub: Ahead of Print]
Examples:
TC#	Name	Organismal Type	Example
9.B.415.1.1	Putative auxiliary subunit, AuxB, of 339 aas and 3 or 4 TMSs. AuxB may be a subunit of a transporter that confers sensitivity to beta-lactams. It shows the same mutant phenotype as AuxA (9.B.144.1.1) (Mikkelsen et al. 2021).		AuxB of Staphylococcus aureus

9.B.415.1.2	DUF4064 domain-containing protein of 152 aas and 3 or 4 TMSs in a 1 + 2 or 3 arrangement.		DUF4064 protein of Gemella bergeri

9.B.415.1.3	Uncharacterized DUF4064 domain-containing protein of 283 aas and 3 N-terminal TMSs in a 1 + 2 arrangement.		UP of Jeotgalicoccus saudimassiliensis

Examples:
TC#	Name	Organismal Type	Example
9.B.415.2.1	Uncharacterized protein of 396 aas and 3 N-terminal TMSs in a 1 + 2 TMS arrangement. This protein may function with TC# 9.B.414.1.4.		UP of Staphylococcus haemolyticus

9.B.415.2.2	Uncharacterized DUF4064 domain-containing protein with 3 N-terminal TMSs in a 1 + 2 TMS arrangement.		UP of Staphylococcus capitis

9.B.415.2.3	Uncharacterized DUF4064 domain-containing protein of 271 aas and 3 or 4 TMSs in a 1 + 2 or 3 TMS arrangement.		UP of Staphylococcus agnetis