BPEI-Induced Delocalization of PBP4 Potentiates β‑Lactams
against MRSA
Posted on 2019-08-23 - 20:29
With its high morbidity rate and
increasing resistance to treatment,
methicillin-resistant Staphylococcus aureus (MRSA)
is a grave concern in the medical field. In methicillin-susceptible
strains, β-lactam antibiotics disable the penicillin binding
proteins (PBPs) that cross-link the bacterial cell wall. However,
methicillin-resistant strains have PBP2a and PBP4, which continue
enzymatic activity in the presence of β-lactam antibiotics.
The activity of PBP2a and PBP4 is linked to the presence of wall teichoic
acid (WTA); thus, WTA has emerged as a target for antibiotic drug
discovery. In this work, we disable WTA in situ using
its anionic phosphodiester backbone to attract cationic branched polyethylenimine
(BPEI). Data show that BPEI removes β-lactam resistance in common
MRSA strains and clinical isolates. Fluorescence microscopy was used
to investigate this mechanism of action. The results indicate that
BPEI prevents the localization of PBP4 to the cell division septum,
thereby changing the cellular morphology and inhibiting cell division.
Although PBP4 is not required for septum formation, proper cell division
and morphology require WTA; BPEI prevents this essential function.
The combination of BPEI and β-lactams is bactericidal and synergistic.
Because BPEI allows us to study the role of WTA in the cell wall without
genetic mutation or altered translocation of biomolecules and/or their
precursors, this approach can help revise existing paradigms regarding
the role of WTA in prokaryotic biochemistry at every growth stage.
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Hill, Melissa
A.; Lam, Anh K.; Reed, Patricia; Harney, Madeline C.; Wilson, Beatrice A.; Moen, Erika L.; et al. (2019). BPEI-Induced Delocalization of PBP4 Potentiates β‑Lactams
against MRSA. ACS Publications. Collection. https://doi.org/10.1021/acs.biochem.9b00523
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AUTHORS (9)
MH
Melissa
A. Hill
AL
Anh K. Lam
PR
Patricia Reed
MH
Madeline C. Harney
BW
Beatrice A. Wilson
EM
Erika L. Moen
SW
Summer N. Wright
MP
Mariana G. Pinho
CR
Charles V. Rice