Article
Microbiology
Gregory S. Basarab, Sandeep Ghorpade, Liezl Gibhard, Rudolf Mueller, Mathew Njoroge, Nashied Peton, Preshendren Govender, Lisa M. Massoudi, Gregory Thomas Robertson, Anne J. Lenaerts, Helena Ingrid Boshoff, Douglas Joerss, Tanya Parish, Thomas F. Durand-Reville, Manos Perros, Vinayak Singh, Kelly Chibale
Summary: This article describes a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis by inhibiting DNA gyrase. The SPT class of compounds operates through a novel mode of inhibition, which is not cross-resistant with other DNA gyrase-inhibiting antibacterials. Compound 22 from the series demonstrated in vitro cidality and intracellular activity against M. tuberculosis. The DNA gyrase mode of action was supported by inhibition of the target in a DNA supercoiling assay and elicitation of an SOS response in M. tuberculosis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Microbiology
Catherine Shelton, Matthew McNeil, Renee Allen, Lindsay Flint, Dara Russell, Bryan Berube, Aaron Korkegian, Yulia Ovechkina, Tanya Parish
Summary: By studying the mutations in specific genes of Mycobacterium tuberculosis, we found that triazolopyrimidines can interact with these genes and confer resistance to the bacteria. These compounds deplete intracellular ATP levels and exhibit activity against intracellular bacteria, but have no effect on human mitochondrial respiration.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Microbiology
Dmitrii Shiriaev, Alina A. Sofronova, Ekaterina A. Berdnikovich, Dmitrii A. Lukianov, Ekaterina S. Komarova, Valeriya Marina, Yuliya Zakalyukina, Mikhail Biryukov, Tinashe P. Maviza, Yan A. Ivanenkov, Petr Sergiev, Ilya A. Osterman, Olga A. Dontsova
Summary: Bacterial type II topoisomerases are targets of many antibiotics, and some bacteria easily develop resistance to fluoroquinolones through mutations in DNA gyrase or topoisomerase IV genes. Nybomycins are compounds that selectively inhibit growth of some Gram-positive FQ-resistant bacteria, but further research is needed on their effectiveness against Gram-negative species.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Microbiology
Jees Sebastian, Anooja Thomas, Carly Levine, Riju Shrestha, Shawn Levy, Hassan Safi, Sri Ram Pentakota, Pradeep Kumar, David Alland
Summary: Tuberculosis requires continued treatment for months to achieve a durable cure. A study identified small hidden subpopulations of Mycobacterium tuberculosis that repeatedly enter a state of drug tolerance and have a predisposition to develop drug resistance. These difficult-to-eliminate subpopulations may explain why tuberculosis treatment requires extended regimens. The findings provide opportunities for genetic and therapeutic approaches to develop shorter and more effective tuberculosis treatments.
Article
Immunology
Fernanda Maruri, Yan Guo, Amondrea Blackman, Yuri F. van der Heijden, Peter F. Rebeiro, Timothy R. Sterling
Summary: The study found that a predominant mutation allele frequency threshold of 2.5% was the most suitable for detecting DNA gyrase mutations that confer ofloxacin resistance in Mtb.
CLINICAL INFECTIOUS DISEASES
(2021)
Review
Immunology
Amala Bhagwat, Aditi Deshpande, Tanya Parish
Summary: This article discusses various approaches and strategies to address drug resistance in tuberculosis, including developing new drugs or drug combinations, improving the efficacy of existing drugs, and understanding the importance of resistance mechanisms and cross-resistance.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Immunology
Karin Hjort, Pontus Juren, Juan Carlos Toro, Sven Hoffner, Dan Andersson, Linus Sandegren
Summary: Whole-genome sequencing of Mycobacterium tuberculosis from a single patient over 9 years of disease and treatment revealed that antibiotic treatment was the main driver of sequence evolution, leading to stepwise accumulation of resistance mutations to various antibiotics. The study highlighted the dynamic nature of M. tuberculosis infection, population structure, and resistance evolution, emphasizing the importance of rapid antibiotic susceptibility tests in combating this pathogen.
JOURNAL OF INFECTIOUS DISEASES
(2022)
Article
Microbiology
Roger Vargas, Luca Freschi, Andrea Spitaleri, Sabira Tahseen, Ivan Barilar, Stefan Niemann, Paolo Miotto, Daniela Maria Cirillo, Claudio U. Koser, Maha R. Farhat
Summary: Antibiotic resistance among bacterial pathogens is a major global health threat, with Mycobacterium tuberculosis complex having the highest resistance rates globally. By analyzing over 31,000 MTBC genomes, it was demonstrated that certain mutations may not confer resistance independently and might require multiple mutations to act together. Understanding the association between specific mutations and resistance through genome analysis can help improve drug susceptibility testing.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Microbiology
Jeewan Thapa, Joseph Yamweka Chizimu, Soyoka Kitamura, Mwangala Lonah Akapelwa, Pondpan Suwanthada, Nami Miura, Jirachaya Toyting, Tomoyasu Nishimura, Naoki Hasegawa, Yukiko Nishiuchi, Stephen V. Gordon, Chie Nakajima, Yasuhiko Suzuki
Summary: This study found that amino acid substitutions in the gyrA of M. avium contribute to fluoroquinolone resistance, shedding light on the role of these substitutions in the development of resistance.
MICROBIOLOGY SPECTRUM
(2023)
Article
Microbiology
Pilar Domenech, Esma Mouhoub, Michael B. Reed
Summary: Effective treatment of drug-resistant tuberculosis requires rapid and accurate determination of antibiotic susceptibility profile. However, there is limited experimental evidence linking uncommon mutations to phenotypic resistance. In this study, a specific mutation (g878a) in the rrs gene of Mycobacterium tuberculosis is investigated, and it is found to confer low-level resistance to streptomycin only. The mutation does not lead to cross-resistance to other aminoglycoside antibiotics and exhibits a fitness defect in vitro. This study provides clarity to the phenotype attributable to this particular mutation, which is valuable for genomics-based diagnostics and clinical management.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Microbiology
Uday S. Ganapathy, Ruben Gonzalez Del Rio, Monica Cacho-Izquierdo, Fatima Ortega, Joel Lelievre, David Barros-Aguirre, Wassihun Wedajo Aragaw, Matthew D. Zimmerman, Marissa Lindman, Veronique Dartois, Martin Gengenbacher, Thomas Dick
Summary: Fluoroquinolones are effective against tuberculosis but have limited clinical use for nontuberculous mycobacteria infections due to drug resistance. Researchers tested alternative DNA gyrase inhibitors and found that the MGI EC/11716 not only works against mycobacterium tuberculosis, but also M. abscessus and M. avium. The study showed that EC/11716 is bactericidal against M. abscessus, effective against drug-tolerant biofilms, and successful in a mouse model of M. abscessus lung infection.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Infectious Diseases
Zhirui Wang, Rui Sun, Cheng Mu, Chunhua Wang, Hui Zhao, Lina Jiang, Hanfang Ju, Wenxi Dai, Fan Zhang
Summary: This study used whole-genome sequencing to determine the molecular characteristics of fluoroquinolone-resistant and multidrug-resistant M. tuberculosis strains in Tianjin, China. The results showed that whole-genome sequencing is an effective diagnostic tool for predicting drug resistance in TB, with high sensitivities for several drugs. The study highlights the importance of using whole-genome sequencing in predicting drug resistance prior to traditional phenotypic drug susceptibility testing.
INFECTION AND DRUG RESISTANCE
(2022)
Article
Microbiology
Hyun Kim, Shigetarou Mori, Tsuyoshi Kenri, Yasuhiko Suzuki
Summary: This study provides a detailed understanding of the molecular mechanism of M. ulcerans DNA gyrase and its contribution to fluoroquinolone resistance in vitro.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Microbiology
Mikael Mansjo, Oskar Karlsson Lindsjo, Christina Gronfors Seeth, Ramona Groenheit, Jim Werngren
Summary: This study reports that the ddn mutation Trp20Stop is exclusively found among DLM and Pa resistant isolates assigned to lineage 4.5 in the Swedish strain collection, indicating the rarity of high-confidence resistance mutations for new and repurposed anti-TB drugs.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Microbiology
Melisa Willby, Paige Chopra, Darrin Lemmer, Katherine Klein, Tracy L. Dalton, David M. Engelthaler, J. Peter Cegielski, James E. Posey
Summary: Fluoroquinolones play a crucial role in the treatment of multidrug-resistant tuberculosis. Mutations in the gyrA gene are associated with different levels of resistance. Understanding the mechanisms behind FQ resistance can lead to strategies for improved treatment success.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Hannah G. Hampton, Simon A. Jackson, Robert D. Fagerlund, Anne I. M. Vogel, Ron L. Dy, Tim R. Blower, Peter C. Fineran
JOURNAL OF MOLECULAR BIOLOGY
(2018)
Article
Chemistry, Medicinal
Elizabeth G. Gibson, Tim R. Blower, Monica Cacho, Ben Bax, James M. Berger, Neil Osheroff
ACS INFECTIOUS DISEASES
(2018)
Article
Biochemistry & Molecular Biology
Tim R. Blower, Afif Bandak, Amy S. Y. Lee, Caroline A. Austin, John L. Nitiss, James M. Berger
NUCLEIC ACIDS RESEARCH
(2019)
Article
Biochemistry & Molecular Biology
Jasmine M. Cross, Tim R. Blower, Alexander D. H. Kingdon, Robert Pal, David M. Picton, James W. Walton
Article
Biochemistry & Molecular Biology
Izaak N. Beck, Ben Usher, Hannah G. Hampton, Peter C. Fineran, Tim R. Blower
BIOCHEMICAL JOURNAL
(2020)
Article
Multidisciplinary Sciences
Yiming Cai, Ben Usher, Claude Gutierrez, Anastasia Tolcan, Moise Mansour, Peter C. Fineran, Ciaran Condon, Olivier Neyrolles, Pierre Genevaux, Tim R. Blower
Article
Virology
Ella V. Rodwell, Nicolas Wenner, Caisey V. Pulford, Yueyi Cai, Arthur Bowers-Barnard, Alison Beckett, Jonathan Rigby, David M. Picton, Tim R. Blower, Nicholas A. Feasey, Jay C. D. Hinton, Blanca M. Perez-Sepulveda
Summary: This study isolated and characterized 32 phages capable of infecting S. Typhimurium and S. Enteritidis from water sources in Malawi and the UK, finding them classified into three major phylogenetic clusters with different geographical distributions and host ranges. Cluster 3, with its 3.b sub-cluster, contained the most novel isolates, representing the first exploration of phages' potential to target the lineages of Salmonella responsible for bloodstream infections in Sub-Saharan Africa.
Article
Biochemistry & Molecular Biology
David M. L. Picton, Yvette A. Luyten, Richard D. Morgan, Andrew Nelson, Darren L. Smith, David T. F. Dryden, Jay C. D. Hinton, Tim R. Blower
Summary: Bacteria have evolved various systems to defend against bacteriophages and mobile genetic elements, with genes often clustered in defense islands. Functional characterization of a defense island in a multidrug resistant plasmid of E. fergusonii has revealed a novel GmrSD-family type IV DNA modification-dependent restriction enzyme, BrxU, that provides robust phage protection. The study also presents the first structure of BrxU and demonstrates its ability to cleave a range of modified DNAs through a multi-step reaction cycle.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
David M. Picton, Joshua D. Harling-Lee, Samuel J. Duffner, Sam C. Went, Richard D. Morgan, Jay C. D. Hinton, Tim R. Blower
Summary: This study identifies a novel transcriptional regulator, BrxR, and investigates its repressor role in bacterial phage defense systems. Structural analysis and bioinformatic analysis reveal the widespread presence of BrxR in bacteria and its co-localization with various phage defense systems.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Elise M. Ling, Arnaud Basle, Ian G. Cowell, Bert van den Berg, Tim R. Blower, Caroline A. Austin
Summary: This study investigates the conformational changes and ATP hydrolysis mechanism of the ATPase domain of human topoisomerase II beta (TOP2B). It reveals that the GHKL domains are similar while the QTK loop can move for product release. Key drug-binding residues and the impact of the N-terminal strap and residue E103 on ATP hydrolysis are also identified.
Article
Multidisciplinary Sciences
Alejandra Guillen-Garcia, Savannah E. R. Gibson, Caleb J. C. Jordan, Venkata K. Ramaswamy, Victoria L. Linthwaite, Elizabeth H. C. Bromley, Adrian P. Brown, David R. W. Hodgson, Tim R. Blower, Jan R. R. Verlet, Matteo T. Degiacomi, Lars-Olof Palsson, Martin J. Cann
Summary: CO2 regulates electronic energy transfer in cyanobacteria by binding to and enhancing the activity of the light-harvesting complex. This finding provides important insights into the regulation of photosynthesis.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Afif F. Bandak, Tim R. Blower, Karin C. Nitiss, Raveena Gupta, Albert Y. Lau, Ria Guha, John L. Nitiss, James M. Berger
Summary: Type II topoisomerases temporarily cleave duplex DNA to control chromosomal organization, and mutations in hTOP2(3) can make the enzyme hypersensitive to the drug etoposide, leading to cell death. Some of these mutations are also found in cancer genome databases. These findings suggest a link between DNA cleavage predisposition and sensitivity to topoisomerase II poisons in cancer cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Afif F. Bandak, Tim R. Blower, Karin C. Nitiss, Viraj Shah, John L. Nitiss, James M. Berger
Summary: The ATPase domains of the enzyme are not required for DNA strand passage, but their loss elevates the enzyme's propensity for DNA damage. The unstructured C-terminal domains and cleavage-prone mutations enhance strand passage activity and sensitivity to the chemotherapeutic agent etoposide. In ATPase-less enzymes, the presence of CTD or mutations promote even greater levels of DNA cleavage.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Izaak N. Beck, David M. Picton, Tim R. Blower
Summary: Researchers have reported the first structure of a core protein, BrxA, from the Bacteriophage Exclusion (BREX) system, which reveals a conserved DNA recognition mechanism similar to other bacteriophage defense systems. This finding provides new insights into the defense mechanisms against bacteriophage infection.
CURRENT RESEARCH IN STRUCTURAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Rachel E. Ashley, Tim R. Blower, James M. Berger, Neil Osheroff