Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532

Ushiyama, Fumihito; Takashima, Hajime; Matsuda, Y.; Ogata, Yuya; Sasamoto, Naoki; Kurimoto-Tsuruta, Risa; Ueki, Kaori; Tanaka-Yamamoto, Nozomi; Endo, Mayumi; Mima, Masashi; Fujita, Komei; Takata, Isao; Tsuji, Satoshi; Yamashita, Haruhiro; Okumura, Hirotoshi; Otake, Katsumasa; Sugiyama, Hiroyuki

doi:10.1016/j.bmc.2020.115964

Cited by 15 publications

(17 citation statements)

References 21 publications

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“…TP0586532 (Fig. 1 ) is a novel non-hydroxamate LpxC inhibitor which has been shown to have a broad spectrum of antibacterial activity against carbapenem-resistant Enterobacteriaceae and exert potent efficacy in murine models of systemic infection, and pneumonia caused by Gram-negative pathogens [ 19 , 20 ]. To investigate the LPS release associated with the bacterial killing activity of antimicrobial agents, the inhibitory effects of TP0586532 on LPS release from K. pneumoniae , which is killed by TP0586532, were examined in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

TP0586532, a non-hydroxamate LpxC inhibitor, reduces LPS release and IL-6 production both in vitro and in vivo

et al. 2022

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UDP-3- O -acyl- N -acetylglucosamine deacetylase (LpxC) is an essential enzyme in the biosynthesis of Lipid A, an active component of lipopolysaccharide (LPS), from UDP-3- O -acyl- N -acetylglicosamine. LPS is a major component of the cell surface of Gram-negative bacteria. LPS is known to be one of causative factors of sepsis and has been associated with high mortality in septic shock. TP0586532 is a novel non-hydroxamate LpxC enzyme inhibitor. In this study, we examined the inhibitory effect of TP0586532 on the LPS release from Klebsiella pneumoniae both in vitro and in vivo. Our results confirmed the inhibitory effect of TP0586532 on LPS release from the pathogenic bacterial species. On the other hand, meropenem and ciprofloxacin increase the level of LPS release. Furthermore, the effects of TP0586532 on LPS release and interleukin (IL)-6 production in the lung were determined using a murine model of pneumonia caused by K. pneumoniae . As observed in the in vitro study, TP0586532 showed the marked inhibitory effect on LPS release in the lungs, whereas meropenem- and ciprofloxacin-treated mice showed higher levels of LPS release and IL-6 production in the lungs as compared to those in the lungs of vehicle-treated mice. Moreover, TP0586532 used in combination with meropenem and ciprofloxacin attenuated the LPS release and IL-6 production induced by meropenem and ciprofloxacin in the lung. These results indicate that the inhibitory effect of TP0586532 on LPS release from pathogenic bacteria might be of benefit in patients with sepsis.

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Section: Introductionmentioning

confidence: 99%

TP0586532, a non-hydroxamate LpxC inhibitor, reduces LPS release and IL-6 production both in vitro and in vivo

et al. 2022

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“…of the ESKAPE pathogens, and other Enterobacteriaceae and nonfermentative Gram-negative bacilli. , Despite the outstanding antibiotic activity of hydroxamate-containing LpxC inhibitors, there have always been concerns due to the poor performance of hydroxamate-containing matrix metalloproteinase (MMP) inhibitors . The failure of Achaogen’s ACHN-975, a hydroxamate-containing LpxC inhibitor, in phase I clinical trials due to adverse cardiovascular effects has cemented such fear and motivated the development of nonhydroxamate LpxC inhibitors, such as the ones developed by Forge Therapeutics , and Taisho Pharmaceutical Co. , Intriguingly, recent work from Achaogen showed that eliminating the hydroxamate group did not mitigate the cardiovascular side effect. Instead, modifications in other parts of the molecule improved the cardiovascular safety window .…”

Section: Future Of Lpxc Inhibitorsmentioning

confidence: 99%

“…Instead, modifications in other parts of the molecule improved the cardiovascular safety window . Conversely, some nonhydroxamate-based LpxC inhibitors similarly displayed an adverse cardiovascular effect (e.g., compounds 17 and 18 in ref ). Taken together, these observations raise an intriguing possibility that compounds with an enhanced potency of LpxC inhibition such as those offered by the difluoromethyl- allo -threonyl-hydroxamate compounds might offer a sufficient window of safety.…”

Section: Future Of Lpxc Inhibitorsmentioning

confidence: 99%

Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria

Zhou

Hong

2021

Acc. Chem. Res.

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Metrics & More Article Recommendations CONSPECTUS: Bacterial infections caused by multi-drug-resistant Gram-negative pathogens pose a serious threat to public health. Gram-negative bacteria are characterized by the enrichment of lipid A-anchored lipopolysaccharide (LPS) or lipooligosaccharide (LOS) in the outer leaflet of their outer membrane. Constitutive biosynthesis of lipid A via the Raetz pathway is essential for bacterial viability and fitness in the human host. The inhibition of early-stage lipid A enzymes such as LpxC not only suppresses the growth of Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter spp., and other clinically important Gram-negative pathogens but also sensitizes these bacteria to other antibiotics. The inhibition of late-stage lipid A enzymes such as LpxH is uniquely advantageous because it has an extra mechanism of bacterial killing through the accumulation of toxic lipid A intermediates, rendering LpxH inhibition additionally lethal to Acinetobacter baumannii. Because essential enzymes of the Raetz pathway have never been exploited by commercial antibiotics, they are excellent targets for the development of novel antibiotics against multi-drugresistant Gram-negative infections. This Account describes the ongoing research on characterizing the structure and inhibition of LpxC and LpxH, the second and fourth enzymes of the Raetz pathway of lipid A biosynthesis, in the laboratories of Dr. Pei Zhou and Dr. Jiyong Hong at Duke University. Our studies have elucidated the molecular basis of LpxC inhibition by the first broad-spectrum inhibitor, CHIR-090, as well as the mechanism underlying its spectrum of activity. Such an analysis has provided a molecular explanation for the broadspectrum antibiotic activity of diacetylene-based LpxC inhibitors. Through the structural and biochemical investigation of LpxC inhibition by diacetylene LpxC inhibitors and the first nanomolar LpxC inhibitor, L-161,240, we have elucidated the intrinsic conformational and dynamics difference in individual LpxC enzymes near the active site. A similar approach has been taken to investigate LpxH inhibition, leading to the establishment of the pharmacophore model of LpxH inhibitors and subsequent structural elucidation of LpxH in complex with its first reported small-molecule inhibitor based on a sulfonyl piperazine scaffold. Intriguingly, although our crystallographic analysis of LpxC-and LpxH-inhibitor complexes detected only a single inhibitor conformation in the crystal lattice, solution NMR studies revealed the existence of multiple ligand conformations that together delineate a cryptic ligand envelope expanding the ligand-binding footprint beyond that observed in the crystal structure. By

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“…UDP-3- O -( R -3-hydroxymyristoyl)- N -acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first, committed step in the biosynthesis of lipid A, a fatty acylated glucosamine disaccharide that anchors lipopolysaccharide (LPS) to the outer membrane of Gram-negative bacteria. − Given that LPS is an essential cell wall component in most Gram-negative pathogens, LpxC is a promising target for antibacterial discovery and many LpxC inhibitors have been developed, the majority of which contain a hydroxamate functional group that chelates the catalytic zinc ion. − Some of these compounds are shown in Figure and include molecules from Merck (L-161,240), Chiron (Chiron-090), and British Biotech (BB-78485) . In addition, several companies including Achaogen, , Pfizer, Novartis, , Entasis, and Taisho Pharma have developed LpxC inhibitors that have in vivo activity in animal models of infection, while the Achaogen compound ACHN-975 was also evaluated in a Phase I clinical trial . However, despite highly promising in vitro and in vivo activity, no LpxC inhibitor has progressed through clinical trials, and efforts are needed to widen the therapeutic window of LpxC inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Structure–Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors

Basak¹,

Li²,

Tao³

et al. 2022

J. Med. Chem.

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UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a promising drug target in Gram-negative bacteria. Previously, we described a correlation between the residence time of inhibitors on Pseudomonas aeruginosa LpxC (paLpxC) and the post-antibiotic effect (PAE) caused by the inhibitors on the growth of P. aeruginosa. Given that drugs with prolonged activity following compound removal may have advantages in dosing regimens, we have explored the structure–kinetic relationship for paLpxC inhibition by analogues of the pyridone methylsulfone PF5081090 (1) originally developed by Pfizer. Several analogues have longer residence times on paLpxC than 1 (41 min) including PT913, which has a residence time of 124 min. PT913 also has a PAE of 4 h, extending the original correlation observed between residence time and PAE. Collectively, the studies provide a platform for the rational modulation of paLpxC inhibitor residence time and the potential development of antibacterial agents that cause prolonged suppression of bacterial growth.

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Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532

Cited by 15 publications

References 21 publications

TP0586532, a non-hydroxamate LpxC inhibitor, reduces LPS release and IL-6 production both in vitro and in vivo

TP0586532, a non-hydroxamate LpxC inhibitor, reduces LPS release and IL-6 production both in vitro and in vivo

Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria

Structure–Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors

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