scholarly journals The Drug-Resistant Variant P167S Expands the Substrate Profile of CTX-M β-Lactamases for Oxyimino-Cephalosporin Antibiotics by Enlarging the Active Site upon Acylation

Biochemistry ◽  
2017 ◽  
Vol 56 (27) ◽  
pp. 3443-3453 ◽  
Author(s):  
Meha P. Patel ◽  
Liya Hu ◽  
Vlatko Stojanoski ◽  
Banumathi Sankaran ◽  
B. V. Venkataram Prasad ◽  
...  
Keyword(s):  
Active Site ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Cephalosporin Antibiotics ◽  
Drug Resistant Variant

scholarly journals Defective Hydrophobic Sliding Mechanism and Active Site Expansion in HIV-1 Protease Drug Resistant Variant Gly48Thr/Leu89Met: Mechanisms for the Loss of Saquinavir Binding Potency

Biochemistry ◽  
2015 ◽  
Vol 54 (2) ◽  
pp. 422-433 ◽  
Author(s):  
Nathan E. Goldfarb ◽  
Meray Ohanessian ◽  
Shyamasri Biswas ◽  
T. Dwight McGee ◽  
Brian P. Mahon ◽  
...  
Keyword(s):  
Active Site ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Sliding Mechanism ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Backbone 1H, 13C, and 15N chemical shift assignment for HIV-1 protease subtypes and multi-drug resistant variant MDR 769

2012 ◽  
Vol 7 (2) ◽  
pp. 199-202 ◽  
Author(s):  
Xi Huang ◽  
Ian Mitchelle S. de Vera ◽  
Angelo M. Veloro ◽  
James R. Rocca ◽  
Carlos Simmerling ◽  
...  
Keyword(s):  
Chemical Shift ◽  
Chemical Shift Assignment ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Shift Assignment ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Extreme Entropy–Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease

2012 ◽  
Vol 7 (9) ◽  
pp. 1536-1546 ◽  
Author(s):  
Nancy M. King ◽  
Moses Prabu-Jeyabalan ◽  
Rajintha M. Bandaranayake ◽  
Madhavi N. L. Nalam ◽  
Ellen A. Nalivaika ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Resistant Variant ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

2018 ◽  
Vol 61 (14) ◽  
pp. 6379-6397 ◽  
Author(s):  
Jian Zhang ◽  
Vasanthanathan Poongavanam ◽  
Dongwei Kang ◽  
Chiara Bertagnin ◽  
Huamei Lu ◽  
...  
Keyword(s):  
Influenza A ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Drug Resistant Variant ◽  
Group 1

scholarly journals Structures of cell wall arabinosyltransferases with the anti-tuberculosis drug ethambutol

Science ◽  
2020 ◽  
Vol 368 (6496) ◽  
pp. 1211-1219 ◽  
Author(s):  
Lu Zhang ◽  
Yao Zhao ◽  
Yan Gao ◽  
Lijie Wu ◽  
Ruogu Gao ◽  
...  
Keyword(s):  
Cell Wall ◽  
Active Site ◽  
Structural Basis ◽  
Drug Resistant ◽  
Cell Wall Synthesis ◽  
X Ray ◽  
Cryo Electron Microscopy ◽  
Donor And Acceptor ◽  
Biochemical Function ◽  
Glycosyl Donor

The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium tuberculosis cell wall synthesis and are recognized as targets for the anti-tuberculosis drug ethambutol. In this study, we determined cryo–electron microscopy and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC complexes in the presence of their glycosyl donor and acceptor substrates and with ethambutol. These structures show how the donor and acceptor substrates bind in the active site and how ethambutol inhibits arabinosyltransferases by binding to the same site as both substrates in EmbB and EmbC. Most drug-resistant mutations are located near the ethambutol binding site. Collectively, our work provides a structural basis for understanding the biochemical function and inhibition of arabinosyltransferases and the development of new anti-tuberculosis agents.

scholarly journals Two Coselected Distal Mutations in HIV-1 Reverse Transcriptase (RT) Alter Susceptibility to Nonnucleoside RT Inhibitors and Nucleoside Analogs

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Paul L. Boyer ◽  
Kevin Melody ◽  
Steven J. Smith ◽  
Linda L. Dunn ◽  
Chris Kline ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Reverse Transcriptase ◽  
Active Site ◽  
Nucleoside Analogs ◽  
Transcriptase Inhibitor ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Hydrophobic Region ◽  
Nnrti Resistance ◽  
Hiv 1

ABSTRACTTwo mutations, G112D and M230I, were selected in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) by a novel nonnucleoside reverse transcriptase inhibitor (NNRTI). G112D is located near the HIV-1 polymerase active site; M230I is located near the hydrophobic region where NNRTIs bind. Thus, M230I could directly interfere with NNRTI binding but G112D could not. Biochemical and virological assays were performed to analyze the effects of these mutations individually and in combination. M230I alone caused a reduction in susceptibility to NNRTIs, while G112D alone did not. The G112D/M230I double mutant was less susceptible to NNRTIs than was M230I alone. In contrast, both mutations affected the ability of RT to incorporate nucleoside analogs. We suggest that the mutations interact with each other via the bound nucleic acid substrate; the nucleic acid forms part of the polymerase active site, which is near G112D. The positioning of the nucleic acid is influenced by its interactions with the “primer grip” region and could be influenced by the M230I mutation.IMPORTANCEAlthough antiretroviral therapy (ART) is highly successful, drug-resistant variants can arise that blunt the efficacy of ART. New inhibitors that are broadly effective against known drug-resistant variants are needed, although such compounds might select for novel resistance mutations that affect the sensitivity of the virus to other compounds. Compound 13 selects for resistance mutations that differ from traditional NNRTI resistance mutations. These mutations cause increased sensitivity to NRTIs, such as AZT.

A novel approach to antiviral therapy for influenza

1999 ◽  
Vol 44 (suppl_2) ◽  
pp. 17-22 ◽  
Author(s):  
Peter M. Colman
Keyword(s):  
Tissue Culture ◽  
Sialic Acid ◽  
Active Site ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Drug Resistant ◽  
Enzyme Active Site ◽  
Natural Ligand

Abstract The influenza glycoprotein, neuraminidase, destroys sialic acid–containing receptors on the surface of infected cells and on progeny virions. This activity facilitates the elution of newly budded virus from the infected cell surface and thus contributes to the viral burden in the host. On the basis of the three–dimensional structure of neuraminidase and the structure of the enzyme—product complex, novel analogues of the product (sialic acid, Neu5Ac) were designed and were shown to be potent inhibitors of neuraminidase in vitro and in vivo. Zanamivir (4–guanidino–Neu5Ac2en) is one of the most potent of the sialic acid analogues described to date. It is broadly inhibitory of all type A and B neuraminidases, probably because one of its design features was the requirement that it should interact only with strain–invariant amino acids inside the active site of the enzyme. Inhibition of neuraminidase translates into antiviral activity in tissue culture, in animal models of influenza and in both experimental and naturally acquired influenza in humans. Zanamivir is a minimal modification of the natural ligand (Neu5Ac) of the enzyme. This feature is expected to minimize the viability of drug–resistant virus that might arise through mutations in the enzyme active site. Studies to date of drug–resistant variants selected in tissue culture confirm this expectation. To deliver zanamivir directly to the lungs of patients the agent has been formulated for inhalation using a modified Diskhaler, which ensures high local concentrations and maximizes inhibition of viral neuraminidase.

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