TY - JOUR
T1 - Impact of ftsz inhibition on the localization of the penicillin binding proteins in methicillin-resistant staphylococcus aureus
AU - Ferrer-González, Edgar
AU - Huh, Hyun
AU - Al-Tameemi, Hassan M.
AU - Boyd, Jeffrey M.
AU - Lee, Sang Hyuk
AU - Pilch, Daniel S.
N1 - Funding Information: This work was supported by NIAID grant 1RO1 AI118874-05 (to D.S.P.) and Department of Energy grant DE-SC0019313 (to S.-H.L.). The Boyd lab is funded by NIAID grant 1R01 AI139100-01 and USDA MRF project NE-1028. Publisher Copyright: © 2021 American Society for Microbiology. All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen of acute clinical importance. Combination treatment with an FtsZ inhibitor potentiates the activity of penicillin binding protein (PBP)-targeting b-lactam antibiotics against MRSA. To explore the mechanism underlying this synergistic behavior, we examined the impact of treatment with the FtsZ inhibitor TXA707 on the spatial localization of the five PBP proteins expressed in MRSA. In the absence of drug treatment, PBP1, PBP2, PBP3, and PBP4 colocalize with FtsZ at the septum, contributing to new cell wall formation. In contrast, PBP2a localizes to distinct foci along the cell periphery. Upon treatment with TXA707, septum formation becomes disrupted, and FtsZ relocalizes away from midcell. PBP1 and PBP3 remain significantly colocalized with FtsZ, while PBP2, PBP4, and PBP2a localize away from FtsZ to specific sites along the periphery of the enlarged cells. We also examined the impact on PBP2a and PBP2 localization of treatment with b-lactam antibiotic oxacillin alone and in synergistic combination with TXA707. Significantly, PBP2a localizes to the septum in approximately 15% of the oxacillin-treated cells, a behavior that likely contributes to the b-lactam resistance of MRSA. Combination treatment with TXA707 causes both PBP2a and PBP2 to localize in malformed septum-like structures. Our collective results suggest that PBP2, PBP4, and PBP2a may function collaboratively in peripheral cell wall repair and maintenance in response to FtsZ inhibition by TXA707. Cotreatment with oxacillin appears to reduce the availability of PBP2a to assist in this repair, thereby rendering the MRSA cells more susceptible to the b-lactam.
AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen of acute clinical importance. Combination treatment with an FtsZ inhibitor potentiates the activity of penicillin binding protein (PBP)-targeting b-lactam antibiotics against MRSA. To explore the mechanism underlying this synergistic behavior, we examined the impact of treatment with the FtsZ inhibitor TXA707 on the spatial localization of the five PBP proteins expressed in MRSA. In the absence of drug treatment, PBP1, PBP2, PBP3, and PBP4 colocalize with FtsZ at the septum, contributing to new cell wall formation. In contrast, PBP2a localizes to distinct foci along the cell periphery. Upon treatment with TXA707, septum formation becomes disrupted, and FtsZ relocalizes away from midcell. PBP1 and PBP3 remain significantly colocalized with FtsZ, while PBP2, PBP4, and PBP2a localize away from FtsZ to specific sites along the periphery of the enlarged cells. We also examined the impact on PBP2a and PBP2 localization of treatment with b-lactam antibiotic oxacillin alone and in synergistic combination with TXA707. Significantly, PBP2a localizes to the septum in approximately 15% of the oxacillin-treated cells, a behavior that likely contributes to the b-lactam resistance of MRSA. Combination treatment with TXA707 causes both PBP2a and PBP2 to localize in malformed septum-like structures. Our collective results suggest that PBP2, PBP4, and PBP2a may function collaboratively in peripheral cell wall repair and maintenance in response to FtsZ inhibition by TXA707. Cotreatment with oxacillin appears to reduce the availability of PBP2a to assist in this repair, thereby rendering the MRSA cells more susceptible to the b-lactam.
KW - Anti-PBP2a antibody
KW - Antibacterial synergy
KW - Fluorescence microscopy
KW - FtsZ inhibitor
KW - MRSA
KW - Oxacillin
KW - PBP2a
KW - Penicillin-binding proteins
KW - Protein localization
KW - Transmission electron microscopy
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U2 - https://doi.org/10.1128/JB.00204-21
DO - https://doi.org/10.1128/JB.00204-21
M3 - Article
C2 - 34031040
SN - 0021-9193
VL - 203
JO - Journal of bacteriology
JF - Journal of bacteriology
IS - 16
M1 - e00204-21
ER -