Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus.

Antimicrobial Agents and Chemotherapy
Rashmi GuptaKyle H Rohde

Abstract

Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones,...Continue Reading

References

Jun 1, 1976·Annals of the Rheumatic Diseases·A E FinkelsteinA Misher
Apr 1, 1995·Trends in Biochemical Sciences·J Roca
Apr 1, 1996·Journal of Bacteriology·J A ChesneyJ R Mahoney
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Feb 13, 2001·Microbes and Infection·S T Howard, T F Byrd
Jul 18, 2002·Antimicrobial Agents and Chemotherapy·Juan-Carlos PalominoFrançoise Portaels
Sep 10, 2002·Journal of Bacteriology·R D FleischmannC M Fraser
Mar 27, 2003·Molecular Microbiology·Christopher M SassettiEric J Rubin
Nov 1, 1962·Journal of Bacteriology·M FORBESE A PEETS
Mar 12, 2004·Journal of the History of Medicine and Allied Sciences·Thomas G Benedek
Dec 13, 2005·Biochemistry. Biokhimii︠a︡·G V Smirnova, O N Oktyabrsky
Mar 29, 2006·Dalton Transactions : an International Journal of Inorganic Chemistry·Petra SchlugaBernhard K Keppler
May 6, 2006·American Journal of Respiratory and Critical Care Medicine·William J BurmanRichard E Chaisson
Feb 6, 2007·American Journal of Respiratory and Critical Care Medicine·David E GriffithUNKNOWN Infectious Disease Society of America
Mar 17, 2007·The Journal of Clinical Investigation·Yukihiro KanekoPradeep K Singh
Jul 13, 2007·Nature Reviews. Cancer·Lloyd Kelland
Jan 8, 2008·Journal of Inorganic Biochemistry·Angela CasiniLuigi Messori
Dec 25, 2008·Nucleic Acids Research·Nicole M BakerAlfonso Mondragón
Jun 4, 2010·PloS One·Nuria AndreuSiouxsie Wiles
Jun 11, 2010·Chemistry & Biology·Yves PommierChristophe Marchand
Jul 15, 2011·Metallomics : Integrated Biometal Science·Susan J Berners-Price, Aleksandra Filipovska
Feb 1, 2012·The Journal of Antimicrobial Chemotherapy·Rachid NessarBrigitte Gicquel
Aug 11, 2012·American Journal of Respiratory and Critical Care Medicine·Go-Eun ChoiWon-Jung Koh
Oct 23, 2012·Methods in Enzymology·Iris KerenKim Lewis
Jan 22, 2013·Chemistry Central Journal·Enrique LimaAriel Guzmán
May 15, 2013·Nature Reviews. Microbiology·Joseph A LemireRaymond J Turner
Aug 1, 2013·Free Radical Biology & Medicine·Jun Lu, Arne Holmgren
Nov 21, 2013·The Journal of Infectious Diseases·Isabelle LeratNicolas Veziris
Nov 29, 2013·Journal of Labelled Compounds & Radiopharmaceuticals·Matthew P AkermanJan Rijn Zeevaart
Dec 24, 2013·Mediterranean Journal of Hematology and Infectious Diseases·Lanfranco FattoriniFederico Giannoni
Feb 7, 2014·The Journal of Antimicrobial Chemotherapy·Florian P MaurerAkos Somoskövi
Feb 18, 2014·BioFactors·Carlo BonchiEmanuela Frangipani
Mar 1, 2014·Biochemistry·Katie J AldredNeil Osheroff
Apr 4, 2014·Journal of the American Chemical Society·Kate J AkermanOrde Q Munro
Jun 12, 2014·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Ophir Bar-OnHannah Blau
Oct 27, 2014·The Journal of Antimicrobial Chemotherapy·Beatriz E FerroJohan W Mouton

❮ Previous
Next ❯

Citations

Mar 10, 2020·ChemMedChem·Clinton G L Veale, Ronel Müller
May 29, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Endika Martín-EncinasConcepción Alonso
Jan 7, 2021·Microorganisms·Ahmed SeddekYuk-Ching Tse-Dinh

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Acinetobacter Infections

Acinetobacter infections have become common in hospitalized patients, especially in the intensive care unit setting and are difficult to treat due to their propensity to develop antimicrobial drug resistance. Discover the latest research on Acinetobacter Infections here.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.