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Your search keyword '"Gallardo-Macias R"' showing total 3 results
Start Over Author "Gallardo-Macias R" Topic drug discovery
3 results on '"Gallardo-Macias R"'

1. Human Microbiome Inspired Antibiotics with Improved β-Lactam Synergy against MDR Staphylococcus aureus.

Author

Chu J, Vila-Farres X, Inoyama D, Gallardo-Macias R, Jaskowski M, Satish S, Freundlich JS, and Brady SF

Subjects
Bacterial Proteins chemistry, Bacterial Proteins genetics, Drug Resistance, Multiple, Bacterial genetics, Drug Synergism, Humans, Methicillin-Resistant Staphylococcus aureus drug effects, Methicillin-Resistant Staphylococcus aureus genetics, Microbial Sensitivity Tests, Models, Molecular, Mutation, Phospholipid Transfer Proteins chemistry, Phospholipid Transfer Proteins genetics, Staphylococcus aureus genetics, Structure-Activity Relationship, Anti-Bacterial Agents pharmacology, Drug Discovery, Drug Resistance, Multiple, Bacterial drug effects, Microbiota, Staphylococcus aureus drug effects, beta-Lactams pharmacology
Abstract

The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria, it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized on the basis of bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here, we describe an SAR campaign around humimycin A that produced humimycin 17S. Compared to humimycin A, 17S is a more potent β-lactam potentiator, has a broader spectrum of activity, which now includes both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE), and did not lead to any detectable resistance when used in combination with a β-lactam. Combinations of β-lactam and humimycin 17S provide a potentially useful long-term MRSA regimen.

Published
2018
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2. Discovery of MRSA active antibiotics using primary sequence from the human microbiome.

Author

Chu J, Vila-Farres X, Inoyama D, Ternei M, Cohen LJ, Gordon EA, Reddy BV, Charlop-Powers Z, Zebroski HA, Gallardo-Macias R, Jaskowski M, Satish S, Park S, Perlin DS, Freundlich JS, and Brady SF

Subjects
Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Biological Products chemical synthesis, Biological Products chemistry, Humans, Lipopeptides chemical synthesis, Lipopeptides chemistry, Lipopeptides genetics, Lipopeptides pharmacology, Methicillin-Resistant Staphylococcus aureus enzymology, Microbial Sensitivity Tests, Molecular Conformation, Peptide Synthases genetics, beta-Lactams agonists, beta-Lactams metabolism, Anti-Bacterial Agents isolation & purification, Anti-Bacterial Agents pharmacology, Biological Products isolation & purification, Biological Products pharmacology, Drug Discovery methods, Methicillin-Resistant Staphylococcus aureus drug effects, Microbiota genetics
Abstract

Here we present a natural product discovery approach, whereby structures are bioinformatically predicted from primary sequence and produced by chemical synthesis (synthetic-bioinformatic natural products, syn-BNPs), circumventing the need for bacterial culture and gene expression. When we applied the approach to nonribosomal peptide synthetase gene clusters from human-associated bacteria, we identified the humimycins. These antibiotics inhibit lipid II flippase and potentiate β-lactam activity against methicillin-resistant Staphylococcus aureus in mice, potentially providing a new treatment regimen., Competing Interests: Financial Interest Statement The authors declare no competing financial interests.

Published
2016
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3. Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase.

Author

Lee WG, Frey KM, Gallardo-Macias R, Spasov KA, Chan AH, Anderson KS, and Jorgensen WL

Subjects
Anti-HIV Agents chemical synthesis, Azabicyclo Compounds chemical synthesis, Azabicyclo Compounds chemistry, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Cell Line, Cell Proliferation drug effects, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, Humans, Models, Molecular, Molecular Structure, Reverse Transcriptase Inhibitors chemical synthesis, Solubility, Structure-Activity Relationship, Triazines chemical synthesis, Triazines chemistry, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Azabicyclo Compounds pharmacology, Bridged Bicyclo Compounds pharmacology, Drug Discovery, HIV drug effects, HIV Reverse Transcriptase antagonists & inhibitors, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology, Triazines pharmacology
Abstract

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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