Digby F Warner

University of Cape Town | UCT · Institute of Infectious Disease & Molecular Medicine (IDM)

Mucosal-associated invariant T (MAIT) cells exhibit an intrinsic ability to recognize and respond to microbial infections. The semi-invariant antigen recognition receptor of MAIT cells specifically detects the non-polymorphic antigen-presenting molecule, major histocompatibility complex class I-related protein 1 (MR1), which primarily binds ribofla...

Pioneering studies linking symptomatic disease and cough-mediated Mycobacterium tuberculosis (Mtb) release established the infectious origin of tuberculosis (TB), simultaneously informing the notion that pathology is a prerequisite for Mtb transmission. Our recent work has challenged this assumption: by sampling TB clinic attendees, we detected equ...

Riboflavin (vitamin B2) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin from dietary sources, certain microbes, including Mycobacterium tuberculosis (Mtb), can biosynthesize riboflavin de novo. Riboflavin precursors have also been implicated in the ac...

Pioneering studies linking symptomatic disease and cough-mediated release of Mycobacterium tuberculosis ( Mtb ) established the infectious origin of tuberculosis (TB), simultaneously informing the pervasive notion that pathology is a prerequisite for Mtb transmission. Our prior work has challenged this assumption: by sampling TB clinic attendees, w...

Two libraries of quinoline‐based hybrids 1‐(7‐chloroquinolin‐4‐yl)‐1H‐pyrazolo[3,4–d]pyrimidin‐4‐amine and 7‐chloro‐N‐phenylquinolin‐4‐amine were synthesized and evaluated for their α‐glucosidase inhibitory and antioxidant properties. Compounds with 4‐methylpiperidine and para‐trifluoromethoxy groups, respectively, showed the most promising α‐gluco...

Nitrothiazole derivatives have been reported to exhibit activity against aerobic, anaerobic, and microaerophilic bacteria. This activity profile makes the nitrothiazole compound class an ideal lead source against Mycobacterium tuberculosis, which flourishes in varied environments with different oxygen concentrations. In this work, we investigated s...

Potential Mycobacterium tuberculosis ( Mtb ) transmission during different pulmonary tuberculosis (TB) disease states is poorly understood. We quantified viable aerosolized Mtb from TB clinic attendees following diagnosis and through six months’ follow-up thereafter. Presumptive TB patients (n=102) were classified by laboratory, radiological, and c...

The current active/latent paradigm of tuberculosis (TB) largely neglects the documented spectrum of disease. Lack of consistency on definitions, terminology and diagnostic criteria for different TB states constrains progress in research and product development required to achieve TB elimination. We reached consensus on a set of conceptual states, r...

Tuberculosis (TB) disease, caused by Mycobacterium tuberculosis ( Mtb ) is the leading cause of death among people with human immunodeficiency virus (HIV) infection. No dual‐target drug is currently being used to simultaneously treat both infections. This work aimed to obtain new multitarget HIV‐TB agents, with the goal of optimizing treatments and...

While N‐acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Re...

There is growing recognition that tuberculosis (TB) infection and disease exists as a spectrum of states beyond the current binary classification of latent and active TB. Our aim was to systematically map and synthesize published conceptual frameworks for TB states. We searched MEDLINE, Embase and EMcare for review articles from 1946 to September 2...

Riboflavin (vitamin B 2 ) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin from dietary sources, certain microbes, including Mycobacterium tuberculosis (Mtb), can biosynthesize riboflavin de novo . Riboflavin precursors have also been implicated in the...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded 'mycobacterial mutasome' - minimally comprising DnaE2 polymerase and ImuA' and ImuB accessory proteins - rema...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – rema...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – rema...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – rema...

Background There is growing recognition that tuberculosis (TB) exists as a spectrum of states beyond the current binary classification of latent and active TB. Our aim was to systematically map and synthesize the proposed alternative conceptual frameworks for TB states from the literature. Methods We systematically searched MEDLINE, Embase and EMca...

Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many antibiotics. DprE1, an essential enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical develop...

Advances in sequencing technologies have enabled unprecedented insights into bacterial genome composition and dynamics. However, the disconnect between the rapid acquisition of genomic data and the (much slower) confirmation of inferred genetic function threatens to widen unless techniques for fast, high‐throughput functional validation can be appl...

Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-positive and -negative bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, ison...

A series of molecules containing bulky lipophilic scaffolds was screened for activity against Mycobacterium tuberculosis and a number of compounds with antimycobacterial activity were identified. The most active compound, (2E)-N-(adamantan-1-yl)-3-phenylprop-2-enamide (C1), has a low micromolar minimum inhibitory concentration, low cytotoxicity (th...

The mycobacterial mutasome which is minimally comprised of ImuA′, ImuB, and DnaE2 proteins — has been implicated in DNA damage–induced mutagenesis in Mycobacterium tuberculosis . ImuB, predicted to enable mutasome function via its interaction with the β clamp, is a catalytically inactive member of the Y–family of DNA polymerases. Like other members...

Compounds containing arylpyrrole‐, 1,2,4‐triazole‐ and hydrazone structural frameworks have been widely studied and demonstrated to exhibit a wide range of pharmacological properties. Herein, an exploratory series of new 1,2,4‐triazole derivatives designed by amalgamation of arylpyrrole and 1,2,4‐triazole structural units via a hydrazone linkage is...

Tuberculosis (TB) imposes a major burden on global public health which is exacerbated by the escalating number of multidrug-resistant (MDR)-TB cases. There is consequently an urgent need for new anti-TB drugs and combination regimens. We have investigated the natural product antibiotic fusidic acid (FA) for repurposing against Mycobacterium tubercu...

Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development...

Rationale: Knowledge of the potential for aerosol release of Mycobacterium tuberculosis (Mtb) during disease, treatment, recovery, and asymptomatic carriage is fundamental to understanding tuberculosis (TB) transmission. Objectives: To quantify viable aerosolized Mtb from TB clinic attendees. Methods: 102 presumptive TB patients from two informal s...

Curcumin is a natural product that has been reported to exhibit myriad pharmacological properties, one of which is antitubercular activity. It demonstrates antitubercular activity by directly inhibiting M.tb and also enhances immune responses that ultimately lead to the elimination of M.tb by macrophages. This natural product is however unstable an...

Tuberculosis (TB) is an infectious disease bedeviled by complexity. This poses myriad challenges for a research ecosystem organized around specialist host- and/or pathogen-focused thrusts. Here, we highlight the key challenges and their implications for developing new tools to control TB.

Herein we report the synthesis of novel compounds inspired by the antimicrobial activities of nitroazole and thiazolidin-4-one based compounds reported in the literature. Target compounds were investigated in vitro for antitubercular, antibacterial, antifungal, and overt cell toxicity properties. All compounds exhibited potent antitubercular activi...

Objective Novel approaches are needed to understand and disrupt Mycobacterium tuberculosis transmission. In this proof-of-concept study, we investigated the use of environmental air samplings to detect and quantify M. tuberculosis in different clinic settings in a high-burden area. Design Cross-sectional, environmental sampling. Setting Primary-c...

Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development...

A recent study identified quinolone-based thiosemicarbazone with an MIC 90 value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone-tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits...

Tuberculosis (TB) is one of the leading causes of death worldwide. Developing new anti-TB compounds using cost-effective processes is critical to reduce TB incidence and accomplish the End TB Strategy milestone. Herein, we describe the synthesis and structure–activity relationships of a library of thirty 7H-Pyrrolo[2,3-d]pyrimidine derivatives prov...

Rationale: Interrupting tuberculosis (TB) transmission requires an improved understanding of how - and when - the causative organism, Mycobacterium tuberculosis (Mtb), is aerosolized. Although cough is commonly assumed to be the dominant source of Mtb aerosols, recent evidence of cough-independent Mtb release implies the contribution of alternativ...

Human breath contains trace amounts of non-volatile organic compounds (NOCs) which might provide non-invasive methods for evaluating individual health. In previous work, we demonstrated that lipids detected in exhaled breath aerosol (EBA) could be used as markers of active tuberculosis (TB). Here, we advanced our analytical platform for characteriz...

A series of 25 new benzothiazole–urea–quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (1H and 13C NMR and IR) and by mass spectrometry (HRMS). In vitro e...

Ethnopharmacological relevance Eight indigenous medicinal plants which are used traditionally for the treatment of tuberculosis (TB), malaria, and associated symptoms, were selected for this study. Aim of study The aim of this study was to evaluate the antiplasmodial and antimycobacterial activities of the organic and aqueous crude extracts of dif...

Background Despite being highly prevalent in hospitalised patients with severe HIV-associated tuberculosis (TB) and sepsis, little is known about the mycobacteriology of Mycobacterium tuberculosis bloodstream infection (MTBBSI). We developed methods to serially measure bacillary load in blood and used these to characterise MTBBSI response to anti-T...

Natural products provide a rich source of potential antimicrobials for treating infectious diseases for which drug resistance has emerged. Foremost among these diseases is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of Staphylococcus aureus, revealed that it...

Tuberculosis (TB) remains a public health crisis, requiring the urgent identification of new anti-mycobacterial drugs. We screened several organic and aqueous marine invertebrate extracts for their in vitro inhibitory activity against the causative organism, Mycobacterium tuberculosis. Here, we report the results obtained for 54 marine invertebrate...

Background: Congregate settings, such as healthcare clinics, may play an essential role in Mycobacterium tuberculosis (Mtb) transmission. Using patient and environmental data, we studied transmission at a primary care clinic in South Africa. Methods: We collected patient movements, cough frequency, and clinical data, and measured indoor carbon d...

Human breath contains trace amounts of non-volatile organic compounds (NOCs) which might inform non-invasive methods for evaluation of individual health. In previous work, we demonstrated that lipids detected in exhaled breath aerosol (EBA) could be used as markers of active tuberculosis (TB). Here, we advanced our analytical platform in characteri...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded 'mycobacterial mutasome', minimally comprising DnaE2 polymerase and ImuA' and ImuB accessory proteins, remain...

Rationale South African adolescents carry a high tuberculosis disease burden. It is not known if schools are high-risk settings for Mycobacterium tuberculosis (MTB) transmission. Objectives To detect airborne MTB genomic DNA in classrooms. Methods We studied 72 classrooms occupied by 1,836 students in two South African schools. High-volume air filt...

Natural products provide a rich source of potential antimicrobials for use in treating infectious diseases for which drug resistance has emerged. Foremost among these is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of Staphylococcus aureus, revealed that it i...

Rationale Interrupting tuberculosis (TB) transmission requires an improved understanding of how – and when – the causative organism, Mycobacterium tuberculosis ( Mtb ), is aerosolized. Although Cough is commonly assumed to be the dominant source of Mtb aerosols, recent evidence of Cough-independent Mtb release implies the contribution of alternativ...

Despite the availability of effective drug treatment, Mycobacterium tuberculosis (Mtb), the causative agent of TB disease, kills ~1. 5 million people annually, and the rising prevalence of drug resistance increasingly threatens to worsen this plight. We previously showed that sublethal exposure to the frontline anti-TB drug, rifampicin, resulted in...

The therapeutic repertoire for tuberculosis (TB) remains limited despite the existence of many TB drugs that are highly active in in vitro models and possess clinical utility. Underlying the lack of efficacy in vivo is the inability of TB drugs to penetrate microenvironments inhabited by the causative agent, Mycobacterium tuberculosis, including ho...

Detection and accurate quantitation of viable Mycobacterium tuberculosis is fundamental to understanding mycobacterial pathogenicity, tuberculosis (TB) disease progression and outcomes; TB transmission; drug action, efficacy and drug resistance. Despite this importance, methods for determining numbers of viable bacilli are limited in accuracy and p...

Five new phenolic siderophores 1–5 were isolated from the organic extract of a culture broth in a modified SGG medium of Pseudomonas sp. UIAU-6B, obtained from sediments collected from the Oyun river in North Central Nigeria. The structure of the new compounds, pseudomonin A–C (1–3) and pseudomobactin A and B (4 and 5) isolated alongside two known...

Life scientists in Africa have had limited opportunity to participate in international advanced scientific training programs and workshops, which largely benefit researchers in North America, Europe and the Asia–Pacific region. Here, we chronicle the strategies adopted and challenges encountered in organizing Imaging Africa, an all-expenses-paid, c...

A series of fourteen 6‐substituted‐2‐(methoxyquinolin‐3‐yl) methyl)‐N‐(pyridin‐3‐ylmethyl) benzamides was prepared from commercially available anilines in five simple and convenient synthetic steps. The structures of all new products were confirmed by routine spectroscopic methods: IR, 1H and 13C NMR, and HRMS (electrospray ionization). The resulti...

Propylphosphonic acid anhydride has been successfully used as a coupling agent in the synthesis of a series of indolizine-2-carboxamido derivatives from indolizine-2-carboxylic acid and its 3-acetylated analogue. The acid substrates were obtained by saponification of the corresponding methyl esters produced, in turn, selectively and efficiently, by...

Detection and accurate quantitation of viable Mycobacterium tuberculosis is fundamental to understanding mycobacterial pathogenicity, tuberculosis (TB) disease progression and outcomes; TB transmission; drug action, efficacy and drug resistance. Despite this importance, methods for determining numbers of viable bacilli are limited in accuracy and p...

Mycobacterium tuberculosis has developed extensive resistance to numerous antimycobacterial agents used in the treatment of tuberculosis. Insufficient intracellular accumulation of active moieties allows for selective survival of mycobacteria with drug resistance mutations and accordingly promotes the development of microbial drug resistance. Disco...

A principal factor that contributes towards the failure to eradicate leishmaniasis and tuberculosis infections is the reduced efficacy of existing chemotherapies, owing to a continuous increase in multidrug-resistant strains of the causative pathogens. This accentuates the dire need to develop new and effective drugs against both plights. A series...

Detection and accurate quantitation of viable Mycobacterium tuberculosis is fundamental to understanding mycobacterial pathogenicity, tuberculosis (TB) disease progression and outcomes; TB transmission; drug action, efficacy and drug resistance. Despite this importance, methods for determining numbers of viable bacilli are limited in accuracy and p...

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, Mycobacterium tu...

Cobalamin is an essential cofactor in all domains of life, yet its biosynthesis is restricted to some bacteria and archaea. Mycobacterium smegmatis, an environmental saprophyte frequently used as surrogate for the obligate human pathogen M. tuberculosis, carries approximately 30 genes predicted to be involved in de novo cobalamin biosynthesis. M. s...