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Author Thomas R Ioerger

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An improved statistical method to identify chemical-genetic interactions by exploiting concentration-dependence.

Esha Dutta, Michael A DeJesus, Nadine Ruecker, Anisha Zaveri, Eun-Ik Koh, Christopher M Sassetti, Dirk Schnappinger, Thomas R Ioerger,

Chemical-genetics (C-G) experiments can be used to identify interactions between inhibitory compounds and bacterial genes, potentially revealing the targets of drugs, or other functionally interacting genes and pathways. C-G experiments involve constructing a library of hypomorphic strains with essential genes that can be knocked-down, treating it with an inhibitory compound, ... Read more >>

PLoS One (PloS one)
[2021, 16(10):e0257911]

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6-Fluorophenylbenzohydrazides inhibit Mycobacterium tuberculosis growth through alteration of tryptophan biosynthesis.

Sara Consalvi, Giulia Venditti, Junhao Zhu, Helena I Boshoff, Kriti Arora, Alessandro De Logu, Thomas R Ioerger, Eric J Rubin, Mariangela Biava, Giovanna Poce,

A major constraint in reducing tuberculosis epidemic is the emergence of strains resistant to one or more of clinically approved antibiotics, which emphasizes the need of novel drugs with novel targets. Genetic knockout strains of Mycobacterium tuberculosis (Mtb) have established that tryptophan (Trp) biosynthesis is essential for the bacterium to ... Read more >>

Eur J Med Chem (European journal of medicinal chemistry)
[2021, 226:113843]

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Characterization of Drug-Resistant Lipid-Dependent Differentially Detectable Mycobacterium tuberculosis.

Annelies W Mesman, Seung-Hun Baek, Chuan-Chin Huang, Young-Mi Kim, Sang-Nae Cho, Thomas R Ioerger, Nadia N Barreda, Roger Calderon, Christopher M Sassetti, Megan B Murray,

An estimated 15-20% of patients who are treated for pulmonary tuberculosis (TB) are culture-negative at the time of diagnosis. Recent work has focused on the existence of differentially detectable <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) bacilli that do not grow under routine solid culture conditions without the addition of supplementary stimuli. We identified ... Read more >>

J Clin Med (Journal of clinical medicine)
[2021, 10(15):]

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Correction to: Natural brominated phenoxyphenols kill persistent and biofilm-incorporated cells of MRSA and other pathogenic bacteria.

Lasse van Geelen, Farnusch Kaschani, Shabnam S Sazzadeh, Emmanuel T Adeniyi, Dieter Meier, Peter Proksch, Klaus Pfeffer, Markus Kaiser, Thomas R Ioerger, Rainer Kalscheuer,

Appl Microbiol Biotechnol (Applied microbiology and biotechnology)
[2021, 105(14-15):6119]

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Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity.

Hongwei Su, Kan Lin, Divya Tiwari, Claire Healy, Carolina Trujillo, Yao Liu, Thomas R Ioerger, Dirk Schnappinger, Sabine Ehrt,

Studying latent Mycobacterium tuberculosis (Mtb) infection has been limited by the lack of a suitable mouse model. We discovered that transient depletion of biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent infections during which Mtb cannot be detected but that relapse in a subset of mice. The ... Read more >>

J Exp Med (The Journal of experimental medicine)
[2021, 218(9):]

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Deletion of Rv2571c confers resistance to arylamide compounds in Mycobacterium tuberculosis.

Catherine D Shelton, Matthew B McNeil, Julie V Early, Thomas R Ioerger, Tanya Parish,

Tuberculosis, caused by <i>Mycobacterium tuberculosis</i>, is an urgent global health problem requiring new drugs, new drug targets and an increased understanding of antibiotic resistance. We have determined the mode of resistance to a series of arylamide compounds in <i>M. tuberculosis</i> We isolated <i>M. tuberculosis</i> resistant mutants to two arylamide compounds ... Read more >>

Antimicrob Agents Chemother (Antimicrobial agents and chemotherapy)
[2021, :]

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Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis.

Charles Omollo, Vinayak Singh, Elizabeth Kigondu, Antonina Wasuna, Pooja Agarwal, Atica Moosa, Thomas R Ioerger, Valerie Mizrahi, Kelly Chibale, Digby F Warner,

Tuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, <i>Mycobacterium tuberculosis</i> We investigated ... Read more >>

Antimicrob Agents Chemother (Antimicrobial agents and chemotherapy)
[2021, :]

Cited: 2 times

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Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus.

Nidja Rehberg, Gereon A Sommer, Daniel Drießen, Marco Kruppa, Emmanuel T Adeniyi, Shang Chen, Lin Wang, Karina Wolf, Boris O A Tasch, Thomas R Ioerger, Kui Zhu, Thomas J J Müller, Rainer Kalscheuer,

Natural bisindole alkaloids such as Hyrtinadine A and Alocasin A, which are known to exhibit diverse bioactivities, provide promising chemical scaffolds for drug development. By optimizing the Masuda borylation-Suzuki coupling sequence, a library of various natural product-derived and non-natural (di)azine-bridged bisindoles was created. While unsubstituted bisindoles were devoid of antibacterial ... Read more >>

J Med Chem (Journal of medicinal chemistry)
[2020, 63(21):12623-12641]

Cited: 1 time

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Cell-Cycle-Associated Expression Patterns Predict Gene Function in Mycobacteria.

Aditya C Bandekar, Sishir Subedi, Thomas R Ioerger, Christopher M Sassetti,

Although the major events in prokaryotic cell cycle progression are likely to be coordinated with transcriptional and metabolic changes, these processes remain poorly characterized. Unlike many rapidly growing bacteria, DNA replication and cell division are temporally resolved in mycobacteria, making these slow-growing organisms a potentially useful system to investigate the ... Read more >>

Curr Biol (Current biology : CB)
[2020, 30(20):3961-3971.e6]

Cited: 1 time

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Distinct Bacterial Pathways Influence the Efficacy of Antibiotics against Mycobacterium tuberculosis.

Michelle M Bellerose, Megan K Proulx, Clare M Smith, Richard E Baker, Thomas R Ioerger, Christopher M Sassetti,

Effective tuberculosis treatment requires at least 6 months of combination therapy. Alterations in the physiological state of the bacterium during infection are thought to reduce drug efficacy and prolong the necessary treatment period, but the nature of these adaptations remain incompletely defined. To identify specific bacterial functions that limit drug ... Read more >>

mSystems (mSystems)
[2020, 5(4):]

Cited: 5 times

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Exploiting Homoplasy in Genome-Wide Association Studies to Enhance Identification of Antibiotic-Resistance Mutations in Bacterial Genomes.

Yi-Pin Lai, Thomas R Ioerger,

Many antibacterial drugs have multiple mechanisms of resistance, which are often represented simultaneously by a mixture of resistance mutations (some more frequent than others) in a clinical population. This presents a challenge for Genome-Wide Association Studies (GWAS) methods, making it difficult to detect less prevalent resistance mechanisms purely through (weak) ... Read more >>

Evol Bioinform Online (Evolutionary bioinformatics online)
[2020, 16:1176934320944932]

Cited: 0 times

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Comprehensive analysis of iron utilization by Mycobacterium tuberculosis.

Lei Zhang, R Curtis Hendrickson, Virginia Meikle, Elliot J Lefkowitz, Thomas R Ioerger, Michael Niederweis,

Iron is essential for nearly all bacterial pathogens, including Mycobacterium tuberculosis (Mtb), but is severely limited in the human host. To meet its iron needs, Mtb secretes siderophores, small molecules with high affinity for iron, and takes up iron-loaded mycobactins (MBT) and carboxymycobactins (cMBT), from the environment. Mtb is also ... Read more >>

PLoS Pathog (PLoS pathogens)
[2020, 16(2):e1008337]

Cited: 7 times

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Global Assessment of Mycobacterium avium subsp. hominissuis Genetic Requirement for Growth and Virulence.

Marte S Dragset, Thomas R Ioerger, Maja Loevenich, Markus Haug, Niruja Sivakumar, Anne Marstad, Pere Joan Cardona, Geir Klinkenberg, Eric J Rubin, Magnus Steigedal, Trude H Flo,

Nontuberculous mycobacterial infections caused by the opportunistic pathogen Mycobacterium avium subsp. hominissuis (MAH) are currently receiving renewed attention due to increased incidence combined with difficult treatment. Insights into the disease-causing mechanisms of this species have been hampered by difficulties in genetic manipulation of the bacteria. Here, we identified and sequenced ... Read more >>

mSystems (mSystems)
[2019, 4(6):]

Cited: 4 times

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Statistical analysis of variability in TnSeq data across conditions using zero-inflated negative binomial regression.

Siddharth Subramaniyam, Michael A DeJesus, Anisha Zaveri, Clare M Smith, Richard E Baker, Sabine Ehrt, Dirk Schnappinger, Christopher M Sassetti, Thomas R Ioerger,

BACKGROUND:Deep sequencing of transposon mutant libraries (or TnSeq) is a powerful method for probing essentiality of genomic loci under different environmental conditions. Various analytical methods have been described for identifying conditionally essential genes whose tolerance for insertions varies between two conditions. However, for large-scale experiments involving many conditions, a method ... Read more >>

BMC Bioinformatics (BMC bioinformatics)
[2019, 20(1):603]

Cited: 3 times

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Mutations in the anti-sigma H factor RshA confer resistance to econazole and clotrimazole in Mycobacterium smegmatis.

Héctor R Morbidoni, Agustina I de la Iglesia, Virginia Figueroa, Cecilia Di Capua, Thomas R Ioerger, Tanya Parish,

Azole drugs such as econazole, are active on <i>Mycobacterium tuberculosis</i> and <i>Mycobacterium smegmatis</i> ; however, the identification of their target(s) is still pending. It has been reported that mutations in the non-essential system <i>mmp</i>L5-<i>mmp</i>S5 conferred resistance to econazole in <i>M. tuberculosis</i> . We herein report that an azole-resistant mutant screen ... Read more >>

Access Microbiol (Access microbiology)
[2019, 1(10):e000070]

Cited: 0 times

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Novel Pyrazole-Containing Compounds Active against Mycobacterium tuberculosis.

Giovanna Poce, Sara Consalvi, Giulia Venditti, Salvatore Alfonso, Nicoletta Desideri, Raquel Fernandez-Menendez, Robert H Bates, Lluis Ballell, David Barros Aguirre, Joaquin Rullas, Alessandro De Logu, Michelle Gardner, Thomas R Ioerger, Eric J Rubin, Mariangela Biava,

In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5-49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile ... Read more >>

ACS Med Chem Lett (ACS medicinal chemistry letters)
[2019, 10(10):1423-1429]

Cited: 4 times

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Genome-wide Phenotypic Profiling Identifies and Categorizes Genes Required for Mycobacterial Low Iron Fitness.

Marte S Dragset, Thomas R Ioerger, Yanjia J Zhang, Mali Mærk, Zekarias Ginbot, James C Sacchettini, Trude H Flo, Eric J Rubin, Magnus Steigedal,

Iron is vital for nearly all living organisms, but during infection, not readily available to pathogens. Infectious bacteria therefore depend on specialized mechanisms to survive when iron is limited. These mechanisms make attractive targets for new drugs. Here, by genome-wide phenotypic profiling, we identify and categorize mycobacterial genes required for ... Read more >>

Sci Rep (Scientific reports)
[2019, 9(1):11394]

Cited: 7 times

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3-O-Methyl-Alkylgallates Inhibit Fatty Acid Desaturation in Mycobacterium tuberculosis.

Nidja Rehberg, Edwin Omeje, Sherif S Ebada, Lasse van Geelen, Zhen Liu, Parichat Sureechatchayan, Matthias U Kassack, Thomas R Ioerger, Peter Proksch, Rainer Kalscheuer,

In the quest for new antibacterial lead structures, activity screening against <i>Mycobacterium tuberculosis</i> identified antitubercular effects of gallic acid derivatives isolated from the Nigerian mistletoe <i>Loranthus micranthus</i> Structure-activity relationship studies indicated that 3-<i>O</i>-methyl-alkylgallates comprising aliphatic ester chains with four to eight carbon atoms showed the strongest growth inhibition <i>in vitro</i> ... Read more >>

Antimicrob Agents Chemother (Antimicrobial agents and chemotherapy)
[2019, 63(9):]

Cited: 1 time

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Correction: TnSeq of Mycobacterium tuberculosis clinical isolates reveals strain-specific antibiotic liabilities.

Allison F Carey, Jeremy M Rock, Inna V Krieger, Michael R Chase, Marta Fernandez-Suarez, Sebastien Gagneux, James C Sacchettini, Thomas R Ioerger, Sarah M Fortune,

[This corrects the article DOI: 10.1371/journal.ppat.1006939.]. ... Read more >>

PLoS Pathog (PLoS pathogens)
[2019, 15(6):e1007846]

Cited: 1 time

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Mycobacterium smegmatis HtrA Blocks the Toxic Activity of a Putative Cell Wall Amidase.

Katherine J Wu, Cara C Boutte, Thomas R Ioerger, Eric J Rubin,

Mycobacterium tuberculosis, the causative agent of tuberculosis, withstands diverse environmental stresses in the host. The periplasmic protease HtrA is required only to survive extreme conditions in most bacteria but is predicted to be essential for normal growth in mycobacteria. We confirm that HtrA is indeed essential in Mycobacterium smegmatis and interacts ... Read more >>

Cell Rep (Cell reports)
[2019, 27(8):2468-2479.e3]

Cited: 4 times

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Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes.

Eachan O Johnson, Emily LaVerriere, Emma Office, Mary Stanley, Elisabeth Meyer, Tomohiko Kawate, James E Gomez, Rebecca E Audette, Nirmalya Bandyopadhyay, Natalia Betancourt, Kayla Delano, Israel Da Silva, Joshua Davis, Christina Gallo, Michelle Gardner, Aaron J Golas, Kristine M Guinn, Sofia Kennedy, Rebecca Korn, Jennifer A McConnell, Caitlin E Moss, Kenan C Murphy, Raymond M Nietupski, Kadamba G Papavinasasundaram, Jessica T Pinkham, Paula A Pino, Megan K Proulx, Nadine Ruecker, Naomi Song, Matthew Thompson, Carolina Trujillo, Shoko Wakabayashi, Joshua B Wallach, Christopher Watson, Thomas R Ioerger, Eric S Lander, Brian K Hubbard, Michael H Serrano-Wu, Sabine Ehrt, Michael Fitzgerald, Eric J Rubin, Christopher M Sassetti, Dirk Schnappinger, Deborah T Hung,

New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen ... Read more >>

Nature (Nature)
[2019, 571(7763):72-78]

Cited: 26 times

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Correlations between secondary structure- and protein-protein interface-mimicry: the interface mimicry hypothesis.

Jaru Taechalertpaisarn, Rui-Liang Lyu, Maritess Arancillo, Chen-Ming Lin, Lisa M Perez, Thomas R Ioerger, Kevin Burgess,

An active segment of the research community designing small molecules ("minimalist mimics" of peptide fragments) to interfere with protein-protein interactions have based their studies on an implicit hypothesis. Here we refer to this as the Secondary Structure Hypothesis, that might be defined as, "If a small molecule can orient amino ... Read more >>

Org Biomol Chem (Organic & biomolecular chemistry)
[2019, 17(12):3267-3274]

Cited: 3 times

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Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition.

Elaine Ballinger, John Mosior, Travis Hartman, Kristin Burns-Huang, Ben Gold, Roxanne Morris, Laurent Goullieux, Isabelle Blanc, Julien Vaubourgeix, Sophie Lagrange, Laurent Fraisse, Stéphanie Sans, Cedric Couturier, Eric Bacqué, Kyu Rhee, Sarah M Scarry, Jeffrey Aubé, Guangbin Yang, Ouathek Ouerfelli, Dirk Schnappinger, Thomas R Ioerger, Curtis A Engelhart, Jennifer A McConnell, Kathrine McAulay, Allison Fay, Christine Roubert, James Sacchettini, Carl Nathan,

<i>Mycobacterium tuberculosis</i> (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb's cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by ... Read more >>

Science (Science (New York, N.Y.))
[2019, 363(6426):]

Cited: 17 times

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Design criteria for minimalist mimics of protein-protein interface segments.

Jaru Taechalertpaisarn, Rui-Liang Lyu, Maritess Arancillo, Chen-Ming Lin, Zhengyang Jiang, Lisa M Perez, Thomas R Ioerger, Kevin Burgess,

Small molecules that can interrupt or inhibit protein-protein interactions (PPIs) are valuable as probes in chemical biology and medicinal chemistry, but they are also notoriously difficult to develop. Design of non-peptidic small molecules that mimic amino acid side-chain interactions in PPIs ("minimalist mimics") is seen as a way to fast ... Read more >>

Org Biomol Chem (Organic & biomolecular chemistry)
[2019, 17(4):908-915]

Cited: 4 times

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A statistical method to identify recombination in bacterial genomes based on SNP incompatibility.

Yi-Pin Lai, Thomas R Ioerger,

<h4>Background</h4>Phylogeny estimation for bacteria is likely to reflect their true evolutionary histories only if they are highly clonal. However, recombination events could occur during evolution for some species. The reconstruction of phylogenetic trees from an alignment without considering recombination could be misleading, since the relationships among strains in some parts ... Read more >>

BMC Bioinformatics (BMC bioinformatics)
[2018, 19(1):450]

Cited: 3 times

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