TY - JOUR
T1 - Targeting a highly conserved domain in bacterial histidine kinases to generate inhibitors with broad spectrum activity
AU - Fihn, Conrad A.
AU - Carlson, Erin E.
N1 - Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/6
Y1 - 2021/6
N2 - With the rise in antimicrobial resistance and the dearth of effective strategies to combat this threat, the development of novel therapies is of utmost importance. Targeting of bacterial signaling through their the two-component systems (TCSs) may be a viable strategy. TCSs are comprisesd of a sensory histidine kinase (HK), of which a bacterium can have up to 160 distinct proteins, and a cognate response regulator (RR). The TCSs are generally non-essential for life, but control many virulence and antibiotic-resistance mechanisms. This, along with their absence in animals makes the TCSs an attractive target for antimicrobial therapy, whether as a stand-alone treatments or adjuvants for existing therapies. This review focuses on progress in the development of inhibitors that target the HK ATP-binding domain. Because this domain is highly conserved, it may be feasible to disrupt multiple TCSs within a single organism to increase effectiveness and reduce pressure for the evolution of resistance.
AB - With the rise in antimicrobial resistance and the dearth of effective strategies to combat this threat, the development of novel therapies is of utmost importance. Targeting of bacterial signaling through their the two-component systems (TCSs) may be a viable strategy. TCSs are comprisesd of a sensory histidine kinase (HK), of which a bacterium can have up to 160 distinct proteins, and a cognate response regulator (RR). The TCSs are generally non-essential for life, but control many virulence and antibiotic-resistance mechanisms. This, along with their absence in animals makes the TCSs an attractive target for antimicrobial therapy, whether as a stand-alone treatments or adjuvants for existing therapies. This review focuses on progress in the development of inhibitors that target the HK ATP-binding domain. Because this domain is highly conserved, it may be feasible to disrupt multiple TCSs within a single organism to increase effectiveness and reduce pressure for the evolution of resistance.
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U2 - 10.1016/j.mib.2021.03.007
DO - 10.1016/j.mib.2021.03.007
M3 - Review article
C2 - 33932730
AN - SCOPUS:85107319162
SN - 1369-5274
VL - 61
SP - 107
EP - 114
JO - Current Opinion in Microbiology
JF - Current Opinion in Microbiology
ER -