About

Thomas R. Ioerger is a Professor in the Department of Computer Science & Engineering at Texas A&M University. He holds a Ph.D. in Computer Science from the University of Illinois at Urbana-Champaign, obtained in 1996, and a B.S. in Molecular and Cell Biology from Pennsylvania State University. His research interests include artificial intelligence, machine learning, intelligent agents, and bioinformatics. He has been recognized as a Faculty Fellow at Texas A&M Engineering Experiment Station and received the Graduate Teaching Excellence Award from the Department of Computer Science at Texas A&M University. His work involves applying computational techniques to biological problems, including gene essentiality analysis, drug target identification, and resistance mechanisms in Mycobacterium tuberculosis.

Research topics

• Biology
• Microbiology
• Virology
• Biochemistry
• Genetics
• Medicine

Selected publications

• Identification and Evaluation of Dibasic Piperidines as Cell Wall Inhibitors against <i>Mycobacterium tuberculosis</i>

  ACS Infectious Diseases · 2026-05-14

  articleOpen access

  remains a significant burden. Although effective treatment regimens exist, drug resistance has continued to emerge. This clinical resistance, combined with side effects and protracted treatment times from the current front-line therapies, means that there is a need to identify novel agents to combat this disease. Here, we report on a new chemical series, identified by whole-cell phenotypic growth inhibition screening, that demonstrates significant activity across multiple media. Mode of action studies indicate that this series targets the same biological pathway as ethambutol (EMB), a drug used in the current front-line treatment of tuberculosis. Screening selected analogues against clinical isolates, resistant to EMB, demonstrated differential sensitivity both across the molecules and against the different specific resistant mutations. The data obtained suggest that this series has potential to be developed into a viable alternative to EMB.

  PublisherDOI

• TnSeq identifies genetic requirements of Mycobacterium tuberculosis for survival under vaccine-induced immunity

  npj Vaccines · 2025-05-22 · 1 citations

  articleOpen access

  Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), remains a persistent global health challenge due to the lack of an effective vaccine. The only licensed TB vaccine, Bacille Calmette-Guerin (BCG), is a live attenuated strain of Mycobacterium bovis that protects young children from severe disease but fails to provide protection through adulthood. It is unclear why BCG provides incomplete protection despite inducing a robust Th1 immune response. We set out to interrogate mycobacterial determinants of vaccine escape using a functional genomics approach, TnSeq, to define bacterial genes required for survival in mice vaccinated with BCG, the live attenuated Mtb vaccine strain, ΔLprG, and in mice with Mtb immunity conferred by prior infection. We find that critical virulence genes associated with acute infection and exponential growth are less essential in hosts with adaptive immunity, including genes encoding the Esx-1 and Mce1 systems. Genetic requirements for Mtb growth in vaccinated and previously Mtb-infected hosts mirror the genetic requirements reported for bacteria under in vitro conditions that reflect aspects of the adaptive immune response. Across distinct immunization conditions, differences in genetic requirements between live attenuated vaccines and vaccination routes are observed, suggesting that different immunization strategies impose distinct bacterial stressors. Collectively, these data support the idea that Mtb requires genes that enable stress adaptation and growth arrest upon encountering the restrictive host environment induced by the adaptive immune response. We demonstrate that TnSeq can be used to understand the bacterial genetic requirements for survival in vaccinated hosts across pre-clinical live attenuated vaccines and therefore may be applied to other vaccine modalities. Understanding how Mtb survives vaccine-induced immunity has the potential to inform the development of new vaccines or adjuvant therapies.

  PublisherOA PDFDOI

• SuFEx-based antitubercular compound irreversibly inhibits Pks13

  Nature · 2025-07-30 · 15 citations

  articleOpen access
  PublisherOA PDFDOI

• Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection in M. tuberculosis clinical isolates

  Tuberculosis · 2025-09-11

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Mutations in the Esx-3 secretion system confer resistance to multiple chemical scaffolds in Mycobacterium tuberculosis

  Microbiology · 2025-11-06

  articleOpen access

  We determined the mechanism of resistance to seven chemical series with potent activity against Mycobacterium tuberculosis . Resistant mutants were isolated against the aminothiazoles, phenylhydrazones, 8-hydroxyquinolines, nitazoxanides, phenyl alkylimidazoles, morpholino thiophenes and trifluoromethyl pyrimidinones. We demonstrated that mutations in several components of the Esx-3 type VII secretion system (EccA3, EccB3, EccC3 and EccD3) conferred resistance to these disparate scaffolds. We conclude that mutations in Esx-3 are a common mechanism of resistance to anti-tubercular agents, which may have clinical relevance for new drugs.

  PublisherDOI

• Identification of a Series Containing a Pentafluorophenyl Moiety That Targets Pks13 to Inhibit Growth of <i>Mycobacterium tuberculosis</i>

  ACS Infectious Diseases · 2025-02-27 · 3 citations

  articleOpen access

  Although not currently in the infectious disease spotlight, there is still a pressing need for new agents to treat tuberculosis caused by Mycobacterium tuberculosis. As there is an ever-increasing amount of clinical resistance to the current drugs, ideally new drugs would be found against novel targets to circumvent pre-existing resistance. A phenotypic growth screen identified a novel singleton, 1, as an inhibitor of M. tuberculosis growth. Mechanism-of-action studies determined that 1 targeted Pks13, an essential enzyme in cell wall biosynthesis that, as of yet, has not been targeted by agents in the clinic. The reactive nature of the pentafluorophenyl warhead meant that the molecule was inherently metabolically unstable. A medicinal chemistry optimization program is described that resulted in the identification of a compound that was reactive enough to still inhibit Pks13 and M. tuberculosis growth while being metabolically stable enough to explore in vivo.

  PublisherOA PDFDOI

• Erratum for Perkowski et al., “The EXIT Strategy: an Approach for Identifying Bacterial Proteins Exported during Host Infection”

  UNC Libraries · 2025-09-17

  articleOpen access

  Erratum for &ldquo;The EXIT Strategy: an Approach for Identifying Bacterial Proteins Exported during Host Infection&rdquo;

  PublisherDOI

• Genome-wide phenotypic insights into mycobacterial virulence using Drosophila melanogaster

  PLoS Pathogens · 2025-09-05 · 3 citations

  articleOpen accessCorresponding

  Drosophila melanogaster (Drosophila) is one of the most extensively studied animal models we have, with a broad, advanced, and organized research community. Yet, Drosophila has barely been exploited to understand the underlying mechanisms of mycobacterial infections, which cause some of the deadliest infectious diseases humans are currently battling. Here, we identified mycobacterial genes required for the pathogen's growth during Drosophila infection. Using Mycobacterium marinum (Mmar) to model mycobacterial pathogens, we first validated that an established mycobacterial virulence factor, EccB1 of the ESX-1 Type VII secretion system, is required for Mmar growth within the flies. Subsequently, we identified Mmar virulence genes in Drosophila in a high-throughput genome-wide phenotypic manner using transposon insertion sequencing. Of the 181 identified virulence genes, the vast majority (91%) had orthologs in the tuberculosis-causing M. tuberculosis (Mtb), suggesting that the encoded virulence mechanisms may be conserved across Mmar and Mtb species. By studying one of the identified genes in more depth, the putative ATP-binding protein ABC transporter encoded by mmar_1660, we found that both the Mmar gene and its Mtb ortholog (rv3041c) were required for virulence in human macrophages as well. We pinpointed the probable virulence mechanism of the genes to their requirements for growth during iron limitation, a condition met by mycobacteria during host infection. Together, our results bring forward Drosophila as a promising host model to study and identify mycobacterial virulence factors, providing insights that may transfer to Mtb human infection.

  PublisherOA PDFDOI

• Interstitial macrophages prevent tuberculosis relapse by restricting <i>Mycobacterium tuberculosis</i> immune evasion

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-31 · 1 citations

  preprintOpen access

  Alveolar macrophages (AMs) are the first immune cells to encounter Mycobacterium tuberculosis (Mtb) in the lungs, but they frequently fail to eliminate this causative agent of tuberculosis (TB), allowing Mtb to persist or replicate. Interstitial macrophages (IMs) are recruited to restrict Mtb growth and limit immune evasion. While IMs have been implicated in the control of acute Mtb infection, their role during latent tuberculosis infection (LTBI) has not yet been explored. We hypothesized that IMs contribute to maintaining latency and that their depletion during LTBI would promote Mtb reactivation, leading to TB relapse and disease. To test this, we utilized our previously established mouse model of paucibacillary Mtb infection that mimics aspects of LTBI in humans to selectively deplete IMs during the latent phase. IM depletion led to TB relapse in 26% of mice compared to 2% in control mice. The transitory depletion of this macrophage subset transiently affected both pulmonary macrophage and neutrophil populations. Mice that relapsed exhibited an increased proportion of pro-inflammatory IMs and elevated concentrations of G-CSF, GM-CSF, IL3, IL-12, IL-13, IL-17A and KC in the lung. These findings indicate that IMs play a critical role in controlling latent Mtb and preventing TB relapse.

  PublisherOA PDFDOI

• Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection in <i>M. tuberculosis</i> clinical isolates

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-12

  preprintOpen access1st authorCorresponding

  Abstract Multiple studies have reported genes in the M. tuberculosis (Mtb) genome that are under diversifying selection, based on genetic variants among Mtb clinical isolates. These might reflect adaptions to selection pressures associated with modern clinical treatment of TB. Many, but not all, of these genes under selection are related to drug resistance. Most of these studies have evaluated selection at the gene-level. However, positive selection can be evaluated on different scales, including individual sites (codons) and local regions within an ORF. In this paper, we use GenomegaMap, a Bayesian method for calculating selection, to evaluate selection of genes in the Mtb genome at all three levels. We present evidence that the intermediate analysis (windows of codons) yields the most credible list of candidate genes under selection (excluding PPE and PE_PGRS genes, which are predicted less reliably due to frequent sequencing errors). A further advantage of this approach is that it identifies specific regions within proteins that are under selective pressure, which is useful for structural and functional interpretation. In an analysis of two separate collections of Mtb clinical isolates (from Moldova; and a globally-representative set), we observed 53 and 173 significant genes under selection, with 36% overlap. The lists of genes under selection include many drug-resistance genes, as well as other genes that have previously been reported to be under selection ( resR, phoR ). The specific regions under selection identified within drug-resistance genes are shown to correspond to protein structural features known to be involved in resistance, supporting accuracy of the method. Positive selection in several ESX-1-related genes was also observed, suggesting adaptation to immune pressure.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21GM059398

  NIH · $203k · 2002

• Decoding the roles of critical genes of unknown function in M. tuberculosis

  NIH · $21.4M · 2013–2019

Frequent coauthors

• James C. Sacchettini

  Texas A&M University

  113 shared

• Chongguang Yang

  Sun Yat-sen University

  65 shared

• Chieh-Yin Wu

  Texas A&M University

  65 shared

• Patrick Cudahy

  65 shared

• Po‐Liang Lu

  Kaohsiung Municipal Ta-Tung Hospital

  65 shared

• Po-Chen Liu

  National Chung Hsing University

  65 shared

• Joshua L. Warren

  Yale University

  65 shared

• Hsiao‐Han Chang

  National Tsing Hua University

  65 shared

Awards & honors

• Faculty Fellow, Texas A&M Engineering Experiment Station (TE…
• Graduate Teaching Excellence Award, Dept. of Computer Scienc…
• Graduate Fellowship, National Science Foundation (NSF) (1990…