2018年10月31日 · Whole-genome sequencing of K. pneumoniae JWM0012 and JWM0013 revealed the presence of mutations in lpxC and fabZ (encoding LpxC V37G /FabZ R121L and LpxC V37G /FabZ F51L, respectively) along with additional mutations (see Table S1 in the supplemental material).

2018年10月31日 · Here we show that serial passaging of Klebsiella pneumoniae in increasing levels of an LpxC inhibitor yielded mutants that grew only in the presence of the inhibitor. These strains had mutations in fabZ and lpxC occurring together (encoding either FabZ R121L /LpxC V37G or FabZ F51L /LpxC V37G).

2023年1月16日 · Here, we perform deep mutational scanning on three essential E. coli proteins (FabZ, LpxC and MurA) involved in cell envelope synthesis using high-throughput CRISPR genome editing, and study the...

2023年4月15日 · FabZ catalyzes the dehydration of R-3-hydroxymyristoyl-ACP and represents a branch point of acyl-ACP going to phospholipid or lipid A biosynthesis. In short, reduction of FabZ activity diverts more acyl-ACP to LPS biosynthesis and on the other hand, increased flux through FabZ favors phospholipid biosynthesis.

2023年8月9日 · Here, we report the development and preclinical characterization of LPC-233, a low-picomolar LpxC inhibitor with outstanding antibiotic activity against a wide range of Gram-negative bacteria in vitro.

2018年10月31日 · Here we show that serial passaging of Klebsiella pneumoniae in increasing levels of an LpxC inhibitor yielded mutants that grew only in the presence of the inhibitor. These strains had mutations in fabZ and lpxC occurring together (encoding either FabZ R121L /LpxC V37G or FabZ F51L /LpxC V37G).

These observations suggest that in fabZ mutants, the mechanism of resistance to LpxC inhibition is restoration of the balance between LPS synthesis and synthesis of phospholipids, reducing flux through both pathways while maintaining the permeability barrier of the outer membrane.

2021年11月26日 · TP0586532 is predicted to exhibit a in vivo efficacy without cardiovascular toxicity and showed the potential of non-hydroxamate LpxC inhibitors as antibacterial agents against...

In this report, we describe the in vitro and in vivo characterization of novel inhibitors of LpxC, an enzyme whose activity is required for proper lipid A biosynthesis, and demonstrate that our lead compound has the requisite attributes to warrant further consideration as a novel antibiotic.

K. pneumoniae fabZ/lpxC mutants escape from inhibitor-dependent growth at high frequency. The lpxC/fabZ mutations harbored by strain JWM0012 confer an inability to grow in the absence of an LpxC inhibitor. To examine the ability to escape from this extreme growth defect, cells were plated for mutant selection on solid medium lacking LpxC inhibitor.