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LpxC inhibitors as new antibacterial agents and tools for studying regulation of lipid A biosynthesis in Gram-negative pathogens.

Tomaras AP, McPherson CJ, Kuhn M, Carifa A, Mullins L, George D, Desbonnet C, Eidem TM, Montgomery JI, Brown MF, Reilly U, Miller AA, O'Donnell JP - MBio (2014)

Bottom Line: New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community.Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane.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.

View Article: PubMed Central - PubMed

Affiliation: Discovery Biology, Antibacterials Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, USA andrew.tomaras@pfizer.com.

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Structures of LpxC inhibitors used in these studies.
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fig1: Structures of LpxC inhibitors used in these studies.

Mentions: Our efforts to identify a potent, broad-spectrum inhibitor of LpxC have focused on a Zn2+ binding class of hydroxamic acids. The structures of the lead molecules from two different series of compounds are shown in Fig. 1. LpxC-2, one of our leads from the biphenyl methylsulfone-containing series, has been described previously (11), as have the pyridone-substituted compounds LpxC-3 and LpxC-4 (12). While the 50% inhibitory concentrations (IC50s) for each of these compounds against the Pseudomonas aeruginosa LpxC enzyme are not substantially different, the pyridone analog LpxC-4 demonstrates a clear MIC90 advantage over the biphenyl analog LpxC-2 when tested against a panel of 106 recent clinical isolates (Table 1). By comparison, despite it having enzyme inhibitory activity roughly equivalent to that of LpxC-4, the MIC90 of CHIR-090, a highly potent LpxC inhibitor that is active against a wide variety of MDR Gram-negative bacteria (13, 14), was found to be 4-fold higher against P. aeruginosa. In the case of Klebsiella pneumoniae, an ~10-fold decrease in the enzyme IC50 between LpxC-3 and LpxC-4 resulted in a 16-fold decrease in MIC90 to 1 µg/ml (Table 1). In Acinetobacter baumannii, however, all LpxC inhibitors tested had considerably higher enzyme IC50s and MIC90 values that were 32 µg/ml or greater. It should be noted, however, that a structurally related LpxC inhibitor from the pyridone class was recently demonstrated to have significant in vivo efficacy against an MDR clinical isolate of A. baumannii despite having no whole-cell activity in vitro (15), a disconnect which is likely due to the unusual ability of A. baumannii to survive in vitro without LPS (16). Many of our compounds, most notably LpxC-4, also have strong activity against other important Gram-negative species, including Escherichia coli, Enterobacter spp., Burkholderia cepacia, and Stenotrophomonas maltophilia (Table 1). Since it proved to be a potent compound with broad-spectrum activity, we chose to further characterize LpxC-4 both in vitro and in vivo.


LpxC inhibitors as new antibacterial agents and tools for studying regulation of lipid A biosynthesis in Gram-negative pathogens.

Tomaras AP, McPherson CJ, Kuhn M, Carifa A, Mullins L, George D, Desbonnet C, Eidem TM, Montgomery JI, Brown MF, Reilly U, Miller AA, O'Donnell JP - MBio (2014)

Structures of LpxC inhibitors used in these studies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196226&req=5

fig1: Structures of LpxC inhibitors used in these studies.
Mentions: Our efforts to identify a potent, broad-spectrum inhibitor of LpxC have focused on a Zn2+ binding class of hydroxamic acids. The structures of the lead molecules from two different series of compounds are shown in Fig. 1. LpxC-2, one of our leads from the biphenyl methylsulfone-containing series, has been described previously (11), as have the pyridone-substituted compounds LpxC-3 and LpxC-4 (12). While the 50% inhibitory concentrations (IC50s) for each of these compounds against the Pseudomonas aeruginosa LpxC enzyme are not substantially different, the pyridone analog LpxC-4 demonstrates a clear MIC90 advantage over the biphenyl analog LpxC-2 when tested against a panel of 106 recent clinical isolates (Table 1). By comparison, despite it having enzyme inhibitory activity roughly equivalent to that of LpxC-4, the MIC90 of CHIR-090, a highly potent LpxC inhibitor that is active against a wide variety of MDR Gram-negative bacteria (13, 14), was found to be 4-fold higher against P. aeruginosa. In the case of Klebsiella pneumoniae, an ~10-fold decrease in the enzyme IC50 between LpxC-3 and LpxC-4 resulted in a 16-fold decrease in MIC90 to 1 µg/ml (Table 1). In Acinetobacter baumannii, however, all LpxC inhibitors tested had considerably higher enzyme IC50s and MIC90 values that were 32 µg/ml or greater. It should be noted, however, that a structurally related LpxC inhibitor from the pyridone class was recently demonstrated to have significant in vivo efficacy against an MDR clinical isolate of A. baumannii despite having no whole-cell activity in vitro (15), a disconnect which is likely due to the unusual ability of A. baumannii to survive in vitro without LPS (16). Many of our compounds, most notably LpxC-4, also have strong activity against other important Gram-negative species, including Escherichia coli, Enterobacter spp., Burkholderia cepacia, and Stenotrophomonas maltophilia (Table 1). Since it proved to be a potent compound with broad-spectrum activity, we chose to further characterize LpxC-4 both in vitro and in vivo.

Bottom Line: New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community.Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane.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.

View Article: PubMed Central - PubMed

Affiliation: Discovery Biology, Antibacterials Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, USA andrew.tomaras@pfizer.com.

Show MeSH
Related in: MedlinePlus