ACS Infectious Diseases Commemorates World Tuberculosis Day 2025: Featured Interviews with Researchers

How was your experience working as a Guest Editor with ACS Infectious Diseases?

Being a guest editor with ACS Infectious Diseases has been an amazing experience. It was a great opportunity to help define the Special Issue's focus, connect with experts, and have the privilege of reading exciting scientific work. The positive response from the community has been truly remarkable. I want to thank the ACS Infectious Diseases editorial team and all the contributing authors for making this such a thoroughly enjoyable and rewarding effort.

Mycobacterial research has very far-reaching implications on Global Research. Could you list 1-2 key areas where upcoming research should focus?

More than a century after its identification as the causative agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb) remains a leading cause of mortality and catastrophic economic devastation in many parts of the world. This persistence is largely attributed to the co-evolution of Mtb with its human host, enabling the bacterium to finely modulate the host system at multiple levels to enhance its survival and transmission. Most of our current understanding of Mtb biology and host interactions is derived from a limited number of strains, such as H37Rv, originally isolated from a patient in 1905. While thousands of Mtb clinical strains have been genotyped, it is now crucial to map phenotypic variations across these strains. Such studies could provide deeper insights into drug resistance patterns, extrapulmonary TB and interactions with HIV and diabetes. The host environment plays a major role in shaping the phenotypic heterogeneity of Mtb, as well as its recalcitrance to antibiotics. A systematic assessment of Mtb’s phenotypic states within tissue niches, along with drug accessibility, in these varying contexts is essential. The preclinical drug discovery pipeline appears well-populated, nevertheless the need for novel drugs with distinct mechanisms of action that could shorten treatment duration remains pressing, as is the dire need for an effective vaccine.

What message would you like to give to the readers of ACS Infectious Diseases?

Infectious diseases remain a major global challenge due to evolving drug resistance and incomplete understanding of the complex host-pathogen interactions. Research on infectious diseases increasingly recognizes the need for an integrated approach that considers pathogen diversity, host interactions, and phenotypic plasticity in diverse chemical environments. A deeper understanding of microbial adaptation in tissue environments will allow identification of sub-populations of host and pathogen phenotypes with different drug responsiveness and susceptibilities, potentially paving the way for targeted solutions and precision medicine. These fundamental breakthroughs could feed into novel drug discovery and treatment strategies.

How was your experience working as a Guest Editor with ACS Infectious Diseases?

Working on a Special Issue closely aligned with your own research interests is always gratifying as you get to interact with others in the field that not only share those interests, but who also share your passion for the subject. With a few exceptions, everybody we approached were keen to contribute. To me, this highlighted the strong bonds in the infectious diseases community and our willingness to give back to the field. With the great support we received from the ACS Infectious Diseases Editorial Team, this was anything but an arduous task.

Mycobacterial research has very far-reaching implications on Global Research. Could you list 1-2 key areas where upcoming research should focus?

One of the biggest challenges in antituberculosis drug discovery is the identification of strategies for treatment shortening, whether through the development of drugs with as yet unexploited targets, or through new combinations or dosing regimens of existing drugs, or other strategies that have remained unexplored thus far. Addressing this challenge will require a multifaceted approach, requiring expertise on the medicinal chemistry of the drugs and drug combinations, as well as the complex biology of this pathogen—especially within the context of the host environment.

Another key area that would benefit from focused research is the development of tools and techniques that can be applied to screen compounds in a medium- or high-throughput manner for uptake by Mtb, and subsequent intracellular target engagement. Getting more data on these aspects will go a long way in helping to direct and ensure the success of new antituberculosis drug development efforts.

What message would you like to give to the readers of ACS Infectious Diseases?

A lot is being said currently in the public domain about the relative importance of research focused on infectious vs non-communicable diseases. As scientists with an interest in and appreciation of the complexities of infectious disease research, we need to ensure that we don’t get drawn into these debates but rather emphasize the close relationship between certain non-communicable diseases and the likelihood of falling victim to an infection. The renewed appreciation of the importance of host-related factors in infectious diseases have highlighted this from our perspective; we need to ensure that those with a focus on non-communicable diseases also understand how infections not just influence, but often also accelerate, the progression of these diseases. We should promote close collaboration as the best way to achieve overall improved human health.

Could you briefly describe your article and its relevance in the field?

DNA topoisomerases, termed ‘Magicians among magicians’, by James Wang for their distinctive reaction mechanism, have continued to be attractive targets for drug discovery. As these enzymes are integral components and participate in central processes of the cell via replication, transcription and other DNA transactions, inhibiting their activity is detrimental to the cells. That the pathogen Mycobacterium tuberculosis has fewer topoisomerases than other bacteria and their indispensability to the organism renders mycobacterial topoisomerases preferred targets for inhibitor development. The article provides an up-to-date comprehensive description of the two topoisomerases—DNA gyrase and Topoisomerase I—found in M. tuberculosis comparing their distinctive properties with that of enzymes from well -studied non -pathogenic organisms. The paper also covers an overview on drug discovery efforts with topoisomerases across bacterial topoisomerases but emphasizing some of the unique approaches employed to exploit mycobacterial enzymes.

How do you look at the next decade for tuberculosis research?

The last three decades have witnessed a surge in tuberculosis research. The sequencing of M. tuberculosis genome in 1998 opened up avenues for in- depth investigations into the structure- activity and intracellular function of a large number of proteins revealing several facets of the pathogen biology and its tricks to outsmart the host. However, there are several unanswered questions on every aspect of pathogen’s biology.In the next decade of research, we are poised to better understand hidden secrets of M. tuberculosis and unravel newer mechanisms of host- pathogen interactions. In parallel, with the significant thrust to find new drugs to replace the currently prescribed treatment regimen, development of drug combinations and shorter duration is the aim to counter resurgent drug-resistant TB strains. A better understanding of proteomics of the bacteria before and after infection, uncovering the new facets of immune modulation should facilitate improved diagnosis of extra—pulmonary TB and more efficient vaccine development.

What message would you like to give to the readers of ACS Infectious Diseases?

As the journal covers broadly every aspect of infectious diseases bridging chemistry and biology, it has attained a unique status among the journals. The researchers, young and old, get to read on a whole range of topics- new metabolic pathways, characterization new enzymes and their reaction mechanism, mechanisms of host pathogen interactions, inhibitor and drug discovery, their delivery, other intervention strategies, drug resistance mechanisms, and allied topics. The multidisciplinary nature within the interface of chemistry and biology provides a new flavour for the readers of the journal to choose the articles of their interest. The reviews, special and thematic issues further enthuse the readers to regularly peruse the journal.

Could you briefly describe your article and its relevance in the field?

We have identified molecules from the 8-hydroxyquinoline series that rapidly kill Mycobacterium tuberculosis in vitro. Our work aimed to determine the target of this series and its mode of action. We demonstrated that the molecules are broadly toxic and act via increased uptake of copper ions into the bacterial cell i.e. they are copper ionophores. This influx of copper has multiple effects on the cell but is toxic and results in cell death. We confirmed that a transient production of oxygen intermediates occurred, which was in part responsible for activity.

How do you look at the next decade for tuberculosis research?

In the next ten years we expect to see several new drugs and regimens enter the tuberculosis clinic; these new agents should shorten therapy to 2-3 months from 4-9 months. Alongside progress in drug discovery and development, we will gain an increased understanding of which bacterial processes and targets are clinically relevant which will allow us to increase our focus on rational drug design. We also expect that there will be a significant improvement in the use of machine learning and AI to predict anti-tubercular activity and drug-like properties which will enable more rapid progression of series through the discovery pipeline.

What message would you like to give to the readers of ACS Infectious Diseases?

Tuberculosis remains an important disease and is a major global health burden. Although the drug pipeline is stronger than in the past, given normal attrition, there is still a major shortfall in R&D for research in therapeutics. We need to increase our efforts to develop new drugs to combat the problem of drug resistance. An increased understanding of the underlying biology of the bacterium can aid us in developing new TB drugs.

Could you briefly describe your article and its relevance in the field?

Caseum that accumulates in the center of necrotic TB lesions is home to nonreplicating persistent (NRP) Mycobacterium tuberculosis (Mtb) that presents a significant hurdle to curing TB. Fluoroquinolones (FQ) such as moxifloxacin are effective at killing NRP Mtb, in contrast to many other TB drugs that primarily kill replicating Mtb. In this article, we examine the potency of alternative gyrase inhibitors in ex vivo caseum and explore a mechanistic rationale for the superiority of FQ. We demonstrate that FQ are unique in their ability to cleave double-stranded DNA at low micromolar concentrations. This study informs the development of more effective chemotherapeutic options against persistent mycobacterial infections.

How do you look at the next decade for tuberculosis research?

Our team envisions that the future of TB chemotherapy will feature new drug regimens capable of reaching and killing all subpopulations of Mtb in the host, thereby improving outcomes and shortening the duration of treatment. To serve this goal, there is a concerted effort in the field to identify and develop clinically relevant in vitro assays and preclinical models that are representative of the full spectrum of human TB disease.

What message would you like to give to the readers of ACS Infectious Diseases?

TB treatment outcomes correlate with disease severity. Hard-to-treat patients with extensive necrosis and cavitation require unique treatment strategies, be it novel inhibitor classes or improved dosing regimens. The development of such strategies will play a key role in the global effort to eradicate TB.

Could you briefly describe your article and its relevance in the field?

Tuberculosis (TB) is a disease of ‘Situation’; and those faced with this situation of Tuberculosis are faced by various barriers towards overcoming it. The article collates obstacles to the elimination of TB highlighting areas for investment of effort by policy makers towards ending TB as proposed by the World Health Organization. The general populace, health care providers and public health managers have a lot of knowledge to glean from this research output in their fight against Tuberculosis.

How do you look at the next decade for tuberculosis research?

With the multiplicity of research innovation and dedicated efforts towards achieving the END TB strategy put in place across all sectors, TB research promises to have advanced and to have tilted towards implementation and translation of facts into problem-solving approaches rather than just theoretical findings

What message would you like to give to the readers of ACS Infectious Diseases?

For the readers of ACS infectious Diseases, you will do well to read more articles from ACS infectious Diseases as you stand the chance of gaining quality information repertoire.

Could you briefly describe your article and its relevance in the field?

Matrix metalloproteinases (MMPs) have emerged as critical mediators in infectious disease research, influencing host-pathogen interactions, immune responses, and disease progression. In tuberculosis (TB), Mycobacterium tuberculosis (Mtb) exploits MMPs to degrade the extracellular matrix (ECM), facilitating bacterial dissemination and granuloma formation. Research into MMP regulation has provided insights into TB pathogenesis, highlighting potential targets for host-directed therapies aimed at mitigating tissue destruction and inflammation. Beyond TB, MMPs are implicated in viral infections (HIV, influenza), bacterial sepsis, and parasitic diseases, where they contribute to immune modulation, pathogen survival, and disease severity. Investigating MMP inhibitors and MMP-responsive drug delivery systems offers a novel avenue for developing adjunctive therapies that can enhance antimicrobial efficacy while reducing host tissue damage. Understanding MMP activity in infectious diseases is pivotal for advancing therapeutic strategies, improving treatment outcomes, and addressing antibiotic resistance by modulating the host environment rather than targeting pathogens directly.

Treating central nervous system tuberculosis (CNS-TB) remains a major challenge due to the restrictive nature of the blood-brain barrier (BBB), which limits drug penetration. Clofazimine (CLF) is effective against Mycobacterium tuberculosis, including multidrug-resistant strains, but its poor physicochemical and pharmacokinetic properties hinder clinical use. This study develops intranasal CLF nano-in-microparticles (CLF-NIMs) to enhance brain drug delivery for CNS-TB treatment. Intranasal administration significantly increased CLF accumulation in brain tissue compared to oral CLF, surpassing the minimum inhibitory concentration. In a murine CNS-TB model, CLF-NIMs reduced brain bacterial burden more effectively than oral CLF. These findings highlight the potential of intranasal nano-based drug delivery to improve TB treatment outcomes, particularly for extra-pulmonary infections. This approach addresses critical challenges in infectious disease therapy by enhancing drug targeting, reducing systemic toxicity, and offering a novel solution for treating TB and other neuro-invasive bacterial infections.

How do you look at the next decade for tuberculosis research?

The next decade of tuberculosis (TB) research is poised for transformative advancements driven by novel therapeutic strategies, improved diagnostics, and enhanced vaccine development. With the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains, there is an urgent need for innovative drug formulations, including host-directed therapies targeting immune modulation and pathogen persistence. Nanotechnology-based drug delivery, such as inhalable nanoparticles and MMP inhibitors, offers promising avenues to enhance drug bioavailability and minimize lung tissue damage. Advancements in molecular diagnostics, such as CRISPR-based detection and AI-driven analysis, will enable early and accurate TB diagnosis, improving treatment outcomes. Additionally, research on next-generation TB vaccines, focusing on long-term immunity and Mtb clearance, will be pivotal. Collaborative global efforts integrating genomics, immunology, and artificial intelligence will accelerate the discovery of effective treatment regimens, making TB eradication a tangible goal in the coming years.

The next decade of tuberculosis (TB) research will focus on advanced drug delivery systems, host-directed therapies, and innovative diagnostics to combat the disease more effectively. Novel approaches like inhalable nanoparticles, intranasal formulations, and long acting injectables will improve targeted therapy, reduce systemic toxicity, and enhance patient compliance. Host-directed therapies (HDTs), including repurposed drugs and immune-modulators, will play a crucial role in modulating the immune response to tackle drug-resistant and persistent infections. Addressing multidrug-resistant TB (MDR-TB) will require new antibiotics, optimized combination regimens, and personalized medicine approaches leveraging pharmacogenomics. Additionally, vaccine development beyond the traditional BCG, including mRNA and protein subunit vaccines, will be a major priority for TB prevention. Advances in early diagnosis through point-of-care testing and biomarker-based detection will enable rapid identification and treatment of extra-pulmonary and latent TB. Artificial intelligence (AI) and big data analytics will further enhance diagnostics, predictive modelling, and epidemiological tracking, driving precision medicine approaches. Interdisciplinary collaborations and technological advancements will be key to achieving global TB eradication.

What message would you like to give to the readers of ACS Infectious Diseases?

To the readers of ACS Infectious Diseases, your work is crucial in addressing global infectious disease challenges. As we combat antimicrobial resistance, emerging pathogens, and persistent infections like tuberculosis, interdisciplinary collaboration is key. Integrating microbiology, chemistry, nanotechnology, and immunology can drive groundbreaking innovations in diagnostics and therapeutics. Host-directed therapies, nanomedicine-based drug delivery, and AI-driven drug discovery hold immense potential for improving treatment outcomes. Advances in omics technologies and biomaterials further enable precise modulation of host-pathogen interactions. These approaches can transform infectious disease management by enhancing drug efficacy and reducing resistance. It is essential to ensure that scientific advancements translate into accessible healthcare solutions. By fostering collaboration, innovation, and evidence-based research, we can revolutionize infectious disease prevention and treatment. Let us remain committed to pioneering solutions that improve patient care and global health, shaping a future where infectious diseases are effectively controlled and eradicated.

Infectious diseases continue to pose a significant global health threat, exacerbated by emerging pathogens, antimicrobial resistance, and challenges in drug delivery. The need for innovative approaches in diagnostics, therapeutics, and targeted drug delivery has never been more urgent. Cutting-edge advancements in nanomedicine, bioengineering, and precision medicine offer promising solutions to enhance treatment efficacy, reduce toxicity, and overcome biological barriers like the blood-brain barrier in CNS infections. Researchers must embrace interdisciplinary collaboration, integrating chemistry, biology, and pharmaceutical sciences to develop clinically translatable interventions. The ACS Infectious Diseases community plays a critical role in driving this progress by sharing ground-breaking research and fostering discussions that shape the future of infectious disease management. I encourage readers to explore novel strategies, challenge existing paradigms, and contribute to the global fight against infectious diseases with a commitment to scientific excellence and translational impact. Together, we can bridge the gap between research and real-world solutions.

Could you briefly describe your article and its relevance in the field?

Mycobacterium tuberculosis caused tuberculosis remains a scourge to human beings. The regulome of transcriptional factor mraZ under hypoxia can serve as a valuable resource for the development of drugs to combat M. tuberculosis infection.

How do you look at the next decade for tuberculosis research?

The AI for life science such as DeepSeek and EVO2 can raise the bar for life sciences, medical biology, and improve our understanding about the life. This holds true for tuberculosis arena too. The cross-sectional collaboration and mindset are crucial for translating the knowledge into better livings. Global networking is also very pivotal to this end, isolation cannot be the solution.

What message would you like to give to the readers of ACS Infectious Diseases?

The journal is very important hub for us to learn the update peer reviewed progresses in the field, and its high-quality publishing can guarantee effective sharing of knowledge.

Could you briefly describe your article and its relevance in the field?

Chorismate mutase (CM) is an enzyme secreted from M. tuberculosis during infection, potentially involved in pathogen-host interactions controlling TB latency. In the shikimate pathway CM catalyzes the Claisen rearrangement of chorismate to prephenate, a biosynthetic precursor to aromatic amino acids. In the 1980’s the Bartlett group at UC Berkley synthesized the first CM inhibitor, a transition state analog. Despite this remarkable achievement progress toward therapeutically practical inhibitors have not progressed, in part due to the unavailability of a robust, scalable assay platform that allows researchers to identify and experimentally validate novel chemical modalities that inhibit CM. To address this bottleneck, we employed RaPID, a mRNA-display screening method to discover CM cyclic peptide ligands. Using one of these ‘chorismides’, we developed a series of sensitive and scalable assays that can detect compounds that modulate the chorismate mutase active site, providing new tools for scientists aiming to further explore this disease critical pathway.

How do you look at the next decade for tuberculosis research?

Research aimed at diagnosis and treatment of TB latency and the development of novel antitubercular drugs to combat resistance appears to remain an unmet challenge. Model organisms to facilitate drug testing would potentially accelerate discovery and validation of new agents. Exploring common points of vulnerability across pathogens may allow more opportunities for TB research.

What message would you like to give to the readers of ACS Infectious Diseases?

We would like to thank ACS Infectious Diseases Editors for organizing and including our manuscript in this Special Issue highlighting the important advances and future directions of M. tuberculosis research. We have a general interest in developing assays to experimentally evaluate compounds derived from modeling, docking or AI algorithms, and potential collaborations with the research community having complimentary areas of expertise.

Could you briefly describe your article and its relevance in the field?

Tuberculosis (TB) remains one of the deadliest infectious diseases, second only to COVID-19 in global mortality. The only widely used TB vaccine, Bacillus Calmette-Guérin (BCG), is over a century old and highly variable in its effectiveness, particularly against adult pulmonary TB. Our recent study, published in ACS Infectious Diseases, explores a new antigenic approach by targeting Mycobacterium tuberculosis transmembrane metal transporter proteins—Cation transporter protein V (CtpV) and Mycobacterial copper transporter B (MctB)—to stimulate a robust immune response.

We successfully expressed and purified these membrane proteins and reconstituted them into proteoliposomes, mimicking their natural environment in the bacterial membrane. This formulation demonstrated a strong Th1-biased immune response in a mouse model, comparable to BCG. To enhance its stability, we encapsulated the proteoliposomes within ZIF-8, a metal-organic framework, ensuring thermostability and eliminating the need for cold-chain storage.

This study highlights the untapped potential of membrane protein antigens in TB vaccine development, moving beyond the traditionally studied soluble and secreted proteins. The results underscore the importance of novel virulence factor and antigen discovery, together with nanoparticle-based delivery methods, in the fight against TB.

How do you look at the next decade for tuberculosis research?

The next decade in tuberculosis research must push beyond the traditional paradigms that have led to decades of stagnant vaccine development. A key shift will be the integration of novel adjuvants designed to enhance mucosal immunity, as TB primarily infects the lungs through airborne transmission. Current injectable vaccines may not provide optimal protection in the respiratory tract, whereas intranasal formulations could induce superior localized immune responses.

Additionally, the future of TB vaccine development lies in exploring antigens beyond the commonly studied secreted proteins. Our research demonstrates that transmembrane proteins, which are actively involved in pathogen survival within the host, could serve as potent immunogenic targets. The approach also substantiates approaches towards targeting key transmembrane virulence factors, such as transition metal and other micronutrient transporters central to nutritional immunity and pathogen intoxication processes. By leveraging advances in synthetic biology, nanoparticle delivery systems, and immune modulation techniques, TB vaccine candidates will likely evolve to elicit stronger, longer-lasting protection.

A concerted effort to develop thermostable formulations will also be crucial, particularly for vaccine distribution in regions with high rates of infection but limited access to refrigeration. Technologies such as MOF encapsulation can revolutionize vaccine logistics and deployment, ensuring that new formulations reach the populations that need them most.

What message would you like to give to the readers of ACS Infectious Diseases?

Eradicating TB will require much more "outside the box" thinking than has historically gone into vaccine development. The field has largely focused on secreted proteins, classical adjuvants, and traditional vaccine schedules, which has led to periodic candidates making it into clinical trials—only to fail to outperform BCG. This cycle of cautious optimism followed by disappointment underscores the need for a radical shift in approach.

Our work suggests that exploring bacterial transmembrane proteins and leveraging advanced delivery mechanisms such as metal-organic frameworks (MOFs) may offer new avenues for durable and effective TB vaccines. The immune system's response to TB is complex, and tackling this challenge will require innovative strategies that simultaneously incorporate antigenic diversity, mucosal immunity enhancement, and thermostable formulations.

It is time to move beyond conventional approaches and embrace novel methodologies. The road ahead is not easy, but by thinking beyond the constraints of traditional vaccine design, we can make meaningful strides toward eliminating tuberculosis as a global health threat.

Could you briefly describe your article and its relevance in the field?

Our review article, "Mycobacterial small heat shock proteins: Dissecting their roles in pathogenesis and development of therapeutics," explores the structural and functional significance of Acr1 (Hsp16.3) and Acr2 (HrpA) in Mycobacterium tuberculosis. These proteins are essential for bacterial survival under stress conditions, contributing to dormancy, resuscitation and immune evasion. This review article provides systematic comprehension of biophysical studies, regulatory mechanisms and their potential applications in diagnostics and therapeutics. While Acr1 is extensively studied for its role in latent tuberculosis (TB) and vaccine development, Acr2 is associated with active TB infection and antibiotic resistance. This review underscores their promise as biomarkers for early tuberculosis detection and as candidates for next-generation vaccines that may enhance or replace the BCG vaccine. By integrating structural biology, immunology and molecular pathogenesis, this article offers new insights into tuberculosis research and potential strategies to combat drug resistance.

How do you look at the next decade for tuberculosis research?

The next decade in tuberculosis research will witness transformative advancements in diagnostics, therapeutics and vaccine development. The rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB will drive the discovery of novel drugs using structure-function driven approaches. Additionally, host-directed therapies and precision medicine will become integral to TB treatment. Cutting-edge innovations in genomics, proteomics and metabolomics will provide deeper insights into host-pathogen interactions during both latent and active TB infection. Next-generation subunit vaccines, including protein- and mRNA-based platforms, will offer enhanced protection and address the limitations of BCG. In particular, Acr1 and Acr2-key regulators of bacterial dormancy, resuscitation and immune evasion-will play a pivotal role in vaccine development. Their integration into recombinant BCG and subunit vaccines could significantly improve TB immunoprevention. A multidisciplinary approach, combining biophysics, immunology and computational biology, will be essential for shaping effective TB eradication strategies in the coming years.

What message would you like to give to the readers of ACS Infectious Diseases?

For the readers of ACS Infectious Diseases, the fight against tuberculosis and other infectious diseases demands relentless innovation and collaboration. With the rise of drug-resistant Mycobacterium tuberculosis, there is an urgent need for novel therapeutic strategies, host-directed interventions and precision medicine. Advances in structural biology, AI-driven drug discovery and microbiome research offer promising avenues for tackling this global health challenge. By integrating cutting-edge science with clinical insights, we can drive transformative breakthroughs in TB diagnosis, treatment and prevention. Together, let’s push the frontiers of research to combat tuberculosis and improve global health.