Acyl chain preference and inhibitor identification of Moraxella catarrhalis LpxA: Insight through crystal structure and computational studies

Pratap, Shivendra; Kesari, Pooja; Yadav, Ravi; Dev, Aditya; Narwal, M.; Kumar, Pravindra

doi:10.1016/j.ijbiomac.2017.01.005

Cited by 10 publications

(9 citation statements)

References 29 publications

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“…Inhibitors of the latter steps in lipid A/LPS synthesis could still prove useful in combination with drugs that normally cannot permeate the asymmetric OM. The most recent studies targeting LPS synthesis have attempted to increase the efficacy of LpxC inhibitors 107 , identify compounds that target LpxA through virtual screening methods 108 ,and develop new high-throughput screening strategies 109,110 for other Lpx enzymes (e.g. LpxH).…”

Section: Inhibitors Of Lps Biogenesis and Modificationmentioning

confidence: 99%

Pushing the envelope: LPS modifications and their consequences

2019

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The defining feature of the Gram-negative cell envelope is the presence of two cellular membranes with the specialized glycolipid lipopolysaccharide (LPS) exclusively found on the surface of the outer membrane. The surface layer of LPS contributes to the stringent permeability properties of the outer membrane which is particularly resistant to permeation of many toxic compounds, including antibiotics. As a common surface antigen, host immune cells recognize LPS and mount defenses to clear pathogenic organisms. To alter properties of the outer membrane or evade the host immune response, Gram-negative bacteria employ a wide variety of chemical modifications to alter LPS. Here we review key features and physiological consequences of LPS biogenesis and modifications.

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Section: Inhibitors Of Lps Biogenesis and Modificationmentioning

confidence: 99%

Pushing the envelope: LPS modifications and their consequences

2019

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“…This enzyme is necessary for bacterial survival and the absence of any homologous protein in humans renders it as a promising target for anti-bacterial drug development. [113][114][115][116] Thus, LpxA is a well-conserved essential enzyme found in most Gram-negative bacteria such as E. coli, P. aeruginosa, K.…”

Section: Lps and Antibiotic Resistancementioning

confidence: 99%

Chemical Highlights Supporting the Role of Lipid A in Efficient Biological Adaptation of Gram-Negative Bacteria to External Stresses

2021

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The outer membrane (OM) of Gram-negative bacteria provides an efficient barrier against external noxious compounds such as antimicrobial agents. Associated with drug target modification it contributes to the overall failure of chemotherapy. In the complex OM architecture, Lipid A plays an essential role by anchoring the lipopolysaccharide in the membrane and ensuring the spatial organization between lipids, proteins, and sugars.Currently, the targets of almost all antibiotics are intracellularly located and required for translocation across membranes. We report herein an integrated view of Lipid A synthesis, membrane assembly, a structure comparison at the molecular structure level of numerous Gram-negative bacterial species as well as its recent use as a target for original antibacterial molecules. This review paves the way for a new vision of a key membrane component that acts during bacterial adaptation to environmental stresses and for the development of new weapons against microbial resistance to usual antibiotics.

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“…as E. coli (Raetz and Roderick, 1995;Williams and Raetz, 2007), and Leptospira interrogans (Robins et al, 2009). More recently, the crystal structure of Moraxella catarrhalis LpxA was determined and potential inhibitors were suggested by presuming that they may also interact with the LpxAs from other gram-negative bacteria (Pratap et al, 2017). When compared to the LpxA, there is a further effort for the development of the LpxC inhibitors (Lee et al, 2011;Kalinin and Holl, 2017).…”

Section: Analysis Of the Prioritized Drug Targetsmentioning

confidence: 99%

Network-Based Metabolism-Centered Screening of Potential Drug Targets in Klebsiella pneumoniae at Genome Scale

Cesur

Siraj

Uddin

et al. 2020

Front. Cell. Infect. Microbiol.

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Klebsiella pneumoniae is an opportunistic bacterial pathogen leading to life-threatening nosocomial infections. Emergence of highly resistant strains poses a major challenge in the management of the infections by healthcare-associated K. pneumoniae isolates. Thus, despite intensive efforts, the current treatment strategies remain insufficient to eradicate such infections. Failure of the conventional infection-prevention and treatment efforts explicitly indicates the requirement of new therapeutic approaches. This prompted us to systematically analyze the K. pneumoniae metabolism to investigate drug targets. Genome-scale metabolic networks (GMNs) facilitating the systematic analysis of the metabolism are promising platforms. Thus, we used a GMN of K. pneumoniae MGH 78578 to determine putative targets through gene-and metabolite-centric approaches. To develop more realistic infection models, we performed the bacterial growth simulations within different host-mimicking media, using an improved biomass formation reaction. We selected more suitable targets based on several property-based prioritization procedures. KdsA was identified as the high-ranked putative target satisfying most of the target prioritization criteria specified under the gene-centric approach. Through a structure-based virtual screening protocol, we identified potential KdsA inhibitors. In addition, the metabolite-centric approach extended the drug target list based on synthetic lethality. This revealed the importance of combined metabolic analyses for a better understanding of the metabolism. To our knowledge, this is the first comprehensive effort on the investigation of the K. pneumoniae metabolism for drug target prediction through the constraint-based analysis of its GMN in conjunction with several bioinformatic approaches. This study can guide the researchers for the future drug designs by providing initial findings regarding crucial components of the Klebsiella metabolism.

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Acyl chain preference and inhibitor identification of Moraxella catarrhalis LpxA: Insight through crystal structure and computational studies

Cited by 10 publications

References 29 publications

Pushing the envelope: LPS modifications and their consequences

Pushing the envelope: LPS modifications and their consequences

Chemical Highlights Supporting the Role of Lipid A in Efficient Biological Adaptation of Gram-Negative Bacteria to External Stresses

Network-Based Metabolism-Centered Screening of Potential Drug Targets in Klebsiella pneumoniae at Genome Scale

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