Mycobacterium tuberculosis PPE51 Inhibits Autophagy by Suppressing Toll-Like Receptor 2-Dependent Signaling.
Autophagy is an ubiquitous homeostatic pathway in mammalian cells and plays a significant role in host immunity. Substantial evidence indicates that the ability of Mycobacterium tuberculosis (Mtb) to successfully evade immune responses is partially due to inhibition of autophagic pathways. Our previous screening of Mtb transposon mutants identified the PPE51 protein as an important autophagy-inhibiting effector. We found that expression of PPE51, either by infecting bacteria or by direct expression in host cells, suppressed responses to potent autophagy-inducing stimuli and interfered with bacterial phagocytosis. This phenotype was associated with reduced activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a key component of signaling pathways that stimulate autophagy. Multiple lines of evidence demonstrated that the effects of PPE51 are attributable to signal blocking by Toll-like receptor 2 (TLR2), a receptor with known involvement of activation of ERK1/2 and autophagy. Consistent with these results, mice with intact TLR2 signaling showed striking virulence attenuation for an Mtb deletion mutant (Δ) compared to wild-type Mtb, whereas infection of TLR2-deficient mice showed no such attenuation. Mice infected with Δ also displayed increased T cell responses to Mtb antigens and increased autophagy in infected lung tissues. Together, these results suggest that TLR2 activates relevant host immune functions during mycobacterial infection, which Mtb then evades through suppression of TLR2 signaling by PPE51. In addition to its previously identified function transporting substrates across the bacterial cell wall, our results demonstrate a direct role of PPE51 for evasion of both innate and adaptive immunity to Mtb. Tuberculosis is a significant global infectious disease caused by infection of the lungs with Mycobacterium tuberculosis, which resides and replicates mainly within host phagocytic cells. During coevolution with humans, Mtb has acquired various mechanisms to inhibit host cellular processes, including autophagy. Autophagy is a complex host cellular process that helps control intracellular infections by enhancing innate and adaptive immune responses. We identified the Mtb protein PPE51 as a mycobacterial effector that inhibits autophagy. We discovered TLR2 and mitogen-activated protein kinase signaling as the axis by which PPE51 mediates this effect. Autophagy regulation by PPE51, along with suppression of other TLR2-activated host cell functions, leads to increased bacterial survival in phagocytic cells and tissues of infected mice. A better understanding of how Mtb regulates autophagy and other host immune effectors could facilitate the design of new therapeutics or vaccines against tuberculosis.
Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes.
Howard Nicole C,Marin Nancy D,Ahmed Mushtaq,Rosa Bruce A,Martin John,Bambouskova Monika,Sergushichev Alexey,Loginicheva Ekaterina,Kurepina Natalia,Rangel-Moreno Javier,Chen Liang,Kreiswirth Barry N,Klein Robyn S,Balada-Llasat Joan-Miquel,Torrelles Jordi B,Amarasinghe Gaya K,Mitreva Makedonka,Artyomov Maxim N,Hsu Fong-Fu,Mathema Barun,Khader Shabaana A
Tuberculosis is a significant global health threat, with one-third of the world's population infected with its causative agent Mycobacterium tuberculosis (Mtb). The emergence of multidrug-resistant (MDR) Mtb that is resistant to the frontline anti-tubercular drugs rifampicin and isoniazid forces treatment with toxic second-line drugs. Currently, ~4% of new and ~21% of previously treated tuberculosis cases are either rifampicin-drug-resistant or MDR Mtb infections. The specific molecular host-pathogen interactions mediating the rapid worldwide spread of MDR Mtb strains remain poorly understood. W-Beijing Mtb strains are highly prevalent throughout the world and associated with increased drug resistance. In the early 1990s, closely related MDR W-Beijing Mtb strains (W strains) were identified in large institutional outbreaks in New York City and caused high mortality rates. The production of interleukin-1β (IL-1β) by macrophages coincides with the shift towards aerobic glycolysis, a metabolic process that mediates protection against drug-susceptible Mtb. Here, using a collection of MDR W-Mtb strains, we demonstrate that the overexpression of Mtb cell wall lipids, phthiocerol dimycocerosates, bypasses the interleukin 1 receptor, type I (IL-1R1) signalling pathway, instead driving the induction of interferon-β (IFN-β) to reprogram macrophage metabolism. Importantly, Mtb carrying a drug resistance-conferring single nucleotide polymorphism in rpoB (H445Y) can modulate host macrophage metabolic reprogramming. These findings transform our mechanistic understanding of how emerging MDR Mtb strains may acquire drug resistance single nucleotide polymorphisms, thereby altering Mtb surface lipid expression and modulating host macrophage metabolic reprogramming.
Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis.
Moreira-Teixeira Lúcia,Tabone Olivier,Graham Christine M,Singhania Akul,Stavropoulos Evangelos,Redford Paul S,Chakravarty Probir,Priestnall Simon L,Suarez-Bonnet Alejandro,Herbert Eleanor,Mayer-Barber Katrin D,Sher Alan,Fonseca Kaori L,Sousa Jeremy,Cá Baltazar,Verma Raman,Haldar Pranabashis,Saraiva Margarida,O'Garra Anne
Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.
A periplasmic cinched protein is required for siderophore secretion and virulence of Mycobacterium tuberculosis.
Iron is essential for growth of Mycobacterium tuberculosis, the causative agent of tuberculosis. To acquire iron from the host, M. tuberculosis uses the siderophores called mycobactins and carboxymycobactins. Here, we show that the rv0455c gene is essential for M. tuberculosis to grow in low-iron medium and that secretion of both mycobactins and carboxymycobactins is drastically reduced in the rv0455c deletion mutant. Both water-soluble and membrane-anchored Rv0455c are functional in siderophore secretion, supporting an intracellular role. Lack of Rv0455c results in siderophore toxicity, a phenotype observed for other siderophore secretion mutants, and severely impairs replication of M. tuberculosis in mice, demonstrating the importance of Rv0455c and siderophore secretion during disease. The crystal structure of a Rv0455c homolog reveals a novel protein fold consisting of a helical bundle with a 'cinch' formed by an essential intramolecular disulfide bond. These findings advance our understanding of the distinct M. tuberculosis siderophore secretion system.
Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection.
Drain Paul K,Bajema Kristina L,Dowdy David,Dheda Keertan,Naidoo Kogieleum,Schumacher Samuel G,Ma Shuyi,Meermeier Erin,Lewinsohn David M,Sherman David R
Clinical microbiology reviews
Tuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium.
Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression.
Sallin Michelle A,Kauffman Keith D,Riou Catherine,Du Bruyn Elsa,Foreman Taylor W,Sakai Shunsuke,Hoft Stella G,Myers Timothy G,Gardina Paul J,Sher Alan,Moore Rashida,Wilder-Kofie Temeri,Moore Ian N,Sette Alessandro,Lindestam Arlehamn Cecilia S,Wilkinson Robert J,Barber Daniel L
Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNγ production is the primary mechanism of CD4 T-cell-mediated protection. However, IFNγ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. In Mtb-infected mice, CD153 expression is highest on Mtb-specific T helper 1 (T1) cells in the lung tissue parenchyma, but its induction does not require T1 cell polarization. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with either Tnfsf8 or Ifng CD4 T cells alone fails to rescue mice from early mortality, but reconstitution with a mixture of Tnfsf8 and Ifng CD4 T cells provides similar protection as wild-type T cells. In Mtb-infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active tuberculosis. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule.
Heterogeneous Host-Pathogen Encounters Coordinate Antibiotic Resilience in Mycobacterium tuberculosis.
Mishra Richa,Yadav Vikas,Guha Madhura,Singh Amit
Trends in microbiology
Successful treatment of tuberculosis (TB) depends on the eradication of its causative agent Mycobacterium tuberculosis (Mtb) in the host. However, the emergence of phenotypically drug-resistant Mtb in the host environment tempers the ability of antibiotics to cure disease. Host immunity produces diverse microenvironmental niches that are exploited by Mtb to mobilize adaptation programs. Such differential interactions amplify pre-existing heterogeneity in the host-pathogen milieu to influence disease pathology and therapy outcome. Therefore, comprehending the intricacies of phenotypic heterogeneity can be an empirical step forward in potentiating drug action. With this goal, we review the interconnectedness of the lesional, cellular, and bacterial heterogeneity underlying phenotypic drug resistance. Based on this information, we anticipate the development of new therapeutic strategies targeting host-pathogen heterogeneity to cure TB.
Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease.
Pollara Gabriele,Turner Carolin T,Rosenheim Joshua,Chandran Aneesh,Bell Lucy C K,Khan Ayesha,Patel Amit,Peralta Luis Felipe,Folino Anna,Akarca Ayse,Venturini Cristina,Baker Tina,Ecker Simone,Ricciardolo Fabio L M,Marafioti Teresa,Ugarte-Gil Cesar,Moore David A J,Chain Benjamin M,Tomlinson Gillian S,Noursadeghi Mahdad
Science translational medicine
Host immune responses at the site of infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (T17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1β and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1β and IL-6 promote T17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.
Antigen-Specific T-Cell Activation Distinguishes between Recent and Remote Tuberculosis Infection.
Mpande Cheleka A M,Musvosvi Munyaradzi,Rozot Virginie,Mosito Boitumelo,Reid Timothy D,Schreuder Constance,Lloyd Tessa,Bilek Nicole,Huang Huang,Obermoser Gerlinde,Davis Mark M,Ruhwald Morten,Hatherill Mark,Scriba Thomas J,Nemes Elisa,
American journal of respiratory and critical care medicine
Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent infection, who should be prioritized for targeted preventive treatment. To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease. South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 mo) and persistent (QuantiFERON-TB+ for >1 yr) infection. We defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-γ TNF -specific T cells and total CD3 T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease and by unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (nonprogressors) or who progressed to microbiologically confirmed disease (progressors). In the test cohorts, frequencies of -specific T cells differentiated between QuantiFERON-TB- ( = 25) and QuantiFERON-TB+ ( = 47) individuals (area under the receiver operating characteristic curve, 0.94; 95% confidence interval, 0.87-1.00). ΔHLA-DR significantly discriminated between recent ( = 20) and persistent ( = 22) QuantiFERON-TB+ (0.91; 0.83-1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis ( = 19; 0.99; 0.96-1.00); and tuberculosis progressors ( = 22) and nonprogressors ( = 34; 0.75; 0.63-0.87). However, ΔHLA-DR median fluorescent intensity could not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67; 0.50-0.84). The ΔHLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted.
Macrophage global metabolomics identifies cholestenone as host/pathogen cometabolite present in human Mycobacterium tuberculosis infection.
Chandra Pallavi,Coullon Héloise,Agarwal Mansi,Goss Charles W,Philips Jennifer A
The Journal of clinical investigation
Mycobacterium tuberculosis (M. tuberculosis) causes an enormous burden of disease worldwide. As a central aspect of its pathogenesis, M. tuberculosis grows in macrophages, and host and microbe influence each other's metabolism. To define the metabolic impact of M. tuberculosis infection, we performed global metabolic profiling of M. tuberculosis-infected macrophages. M. tuberculosis induced metabolic hallmarks of inflammatory macrophages and a prominent signature of cholesterol metabolism. We found that infected macrophages accumulate cholestenone, a mycobacterial-derived, oxidized derivative of cholesterol. We demonstrated that the accumulation of cholestenone in infected macrophages depended on the M. tuberculosis enzyme 3β-hydroxysteroid dehydrogenase (3β-Hsd) and correlated with pathogen burden. Because cholestenone is not a substantial human metabolite, we hypothesized it might be diagnostic of M. tuberculosis infection in clinical samples. Indeed, in 2 geographically distinct cohorts, sputum cholestenone levels distinguished subjects with tuberculosis (TB) from TB-negative controls who presented with TB-like symptoms. We also found country-specific detection of cholestenone in plasma samples from M. tuberculosis-infected subjects. While cholestenone was previously thought to be an intermediate required for cholesterol degradation by M. tuberculosis, we found that M. tuberculosis can utilize cholesterol for growth without making cholestenone. Thus, the accumulation of cholestenone in clinical samples suggests it has an alternative role in pathogenesis and could be a clinically useful biomarker of TB infection.
Development of New Tuberculosis Drugs: Translation to Regimen Composition for Drug-Sensitive and Multidrug-Resistant Tuberculosis.
Ernest Jacqueline P,Strydom Natasha,Wang Qianwen,Zhang Nan,Nuermberger Eric,Dartois Véronique,Savic Rada M
Annual review of pharmacology and toxicology
Tuberculosis (TB) kills more people than any other infectious disease. Challenges for developing better treatments include the complex pathology due to within-host immune dynamics, interpatient variability in disease severity and drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of resistance. Model-informed drug development using quantitative and translational pharmacology has become increasingly recognized as a method capable of drug prioritization and regimen optimization to efficiently progress compounds through TB drug development phases. In this review, we examine translational models and tools, including plasma PK scaling, site-of-disease lesion PK, host-immune and bacteria interplay, combination PK-PD models of multidrug regimens, resistance formation, and integration of data across nonclinical and clinical phases.We propose a workflow that integrates these tools with computational platforms to identify drug combinations that have the potential to accelerate sterilization, reduce relapse rates, and limit the emergence of resistance.
Mechanisms of Drug-Induced Tolerance in Mycobacterium tuberculosis.
Goossens Sander N,Sampson Samantha L,Van Rie Annelies
Clinical microbiology reviews
Successful treatment of tuberculosis (TB) can be hampered by populations that are temporarily able to survive antibiotic pressure in the absence of drug resistance-conferring mutations, a phenomenon termed drug tolerance. We summarize findings on tolerance published in the past 20 years. Key responses to drug pressure are reduced growth rates, metabolic shifting, and the promotion of efflux pump activity. Metabolic shifts upon drug pressure mainly occur in 's lipid metabolism and redox homeostasis, with reduced tricarboxylic acid cycle activity in favor of lipid anabolism. Increased lipid anabolism plays a role in cell wall thickening, which reduces sensitivity to most TB drugs. In addition to these general mechanisms, drug-specific mechanisms have been described. Upon isoniazid exposure, reprograms several pathways associated with mycolic acid biosynthesis. Upon rifampicin exposure, upregulates the expression of its drug target Upon bedaquiline exposure, ATP synthesis is stimulated, and the transcription factors Rv0324 and Rv0880 are activated. A better understanding of 's responses to drug pressure will be important for the development of novel agents that prevent the development of drug tolerance following treatment initiation. Such agents could then contribute to novel TB treatment-shortening strategies.
Functional Signatures of Human CD4 and CD8 T Cell Responses to Mycobacterium tuberculosis.
Prezzemolo Teresa,Guggino Giuliana,La Manna Marco Pio,Di Liberto Diana,Dieli Francesco,Caccamo Nadia
Frontiers in immunology
With 1.4 million deaths and 8.7 million new cases in 2011, tuberculosis (TB) remains a global health care problem and together with HIV and Malaria represents one of the three infectious diseases world-wide. Control of the global TB epidemic has been impaired by the lack of an effective vaccine, by the emergence of drug-resistant forms of Mycobacterium tuberculosis (Mtb) and by the lack of sensitive and rapid diagnostics. It is estimated, by epidemiological reports, that one third of the world's population is latently infected with Mtb, but the majority of infected individuals develop long-lived protective immunity, which controls and contains Mtb in a T cell-dependent manner. Development of TB disease results from interactions among the environment, the host, and the pathogen, and known risk factors include HIV co-infection, immunodeficiency, diabetes mellitus, overcrowding, malnutrition, and general poverty; therefore, an effective T cell response determines whether the infection resolves or develops into clinically evident disease. Consequently, there is great interest in determining which T cells subsets mediate anti-mycobacterial immunity, delineating their effector functions. On the other hand, many aspects remain unsolved in understanding why some individuals are protected from Mtb infection while others go on to develop disease. Several studies have demonstrated that CD4(+) T cells are involved in protection against Mtb, as supported by the evidence that CD4(+) T cell depletion is responsible for Mtb reactivation in HIV-infected individuals. There are many subsets of CD4(+) T cells, such as T-helper 1 (Th1), Th2, Th17, and regulatory T cells (Tregs), and all these subsets co-operate or interfere with each other to control infection; the dominant subset may differ between active and latent Mtb infection cases. Mtb-specific-CD4(+) Th1 cell response is considered to have a protective role for the ability to produce cytokines such as IFN-γ or TNF-α that contribute to the recruitment and activation of innate immune cells, like monocytes and granulocytes. Thus, while other antigen (Ag)-specific T cells such as CD8(+) T cells, natural killer (NK) cells, γδ T cells, and CD1-restricted T cells can also produce IFN-γ during Mtb infection, they cannot compensate for the lack of CD4(+) T cells. The detection of Ag-specific cytokine production by intracellular cytokine staining (ICS) and the use of flow cytometry techniques are a common routine that supports the studies aimed at focusing the role of the immune system in infectious diseases. Flow cytometry permits to evaluate simultaneously the presence of different cytokines that can delineate different subsets of cells as having "multifunctional/polyfunctional" profile. It has been proposed that polyfunctional T cells, are associated with protective immunity toward Mtb, in particular it has been highlighted that the number of Mtb-specific T cells producing a combination of IFN-γ, IL-2, and/or TNF-α may be correlated with the mycobacterial load, while other studies have associated the presence of this particular functional profile as marker of TB disease activity. Although the role of CD8 T cells in TB is less clear than CD4 T cells, they are generally considered to contribute to optimal immunity and protection. CD8 T cells possess a number of anti-microbial effector mechanisms that are less prominent or absent in CD4 Th1 and Th17 T cells. The interest in studying CD8 T cells that are either MHC-class Ia or MHC-class Ib-restricted, has gained more attention. These studies include the role of HLA-E-restricted cells, lung mucosal-associated invariant T-cells (MAIT), and CD1-restricted cells. Nevertheless, the knowledge about the role of CD8(+) T cells in Mtb infection is relatively new and recent studies have delineated that CD8 T cells, which display a functional profile termed "multifunctional," can be a better marker of protection in TB than CD4(+) T cells. Their effector mechanisms could contribute to control Mtb infection, as upon activation, CD8 T cells release cytokines or cytotoxic molecules, which cause apoptosis of target cells. Taken together, the balance of the immune response in the control of infection and possibly bacterial eradication is important in understanding whether the host immune response will be appropriate in contrasting the infection or not, and, consequently, the inability of the immune response, will determine the dissemination and the transmission of bacilli to new subjects. In conclusion, the recent highlights on the role of different functional signatures of T cell subsets in the immune response toward Mtb infection will be discerned in this review, in order to summarize what is known about the immune response in human TB. In particular, we will discuss the role of CD4 and CD8 T cells in contrasting the advance of the intracellular pathogen in already infected people or the progression to active disease in subjects with latent infection. All the information will be aimed at increasing the knowledge of this complex disease in order to improve diagnosis, prognosis, drug treatment, and vaccination.
The Innate Immune Response to Infection.
Ravesloot-Chávez Mariëtta M,Van Dis Erik,Stanley Sarah A
Annual review of immunology
Infection with causes >1.5 million deaths worldwide annually. Innate immune cells are the first to encounter , and their response dictates the course of infection. Dendritic cells (DCs) activate the adaptive response and determine its characteristics. Macrophages are responsible both for exerting cell-intrinsic antimicrobial control and for initiating and maintaining inflammation. The inflammatory response to infection is a double-edged sword. While cytokines such as TNF-α and IL-1 are important for protection, either excessive or insufficient cytokine production results in progressive disease. Furthermore, neutrophils-cells normally associated with control of bacterial infection-are emerging as key drivers of a hyperinflammatory response that results in host mortality. The roles of other innate cells, including natural killer cells and innate-like T cells, remain enigmatic. Understanding the nuances of both cell-intrinsic control of infection and regulation of inflammation will be crucial for the successful development of host-targeted therapeutics and vaccines.
Efflux pumps in Mycobacterium tuberculosis and their inhibition to tackle antimicrobial resistance.
Laws Mark,Jin Peiqin,Rahman Khondaker Miraz
Trends in microbiology
Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis, was the leading cause of mortality worldwide in 2019 due to a single infectious agent. The growing threat of strains of M. tuberculosis untreatable by modern antibiotic regimens only exacerbates this problem. In response to this continued public health emergency, research into methods of potentiating currently approved antimicrobial agents against resistant strains of M. tuberculosis is an urgent priority, and a key strategy in this regard is the design of mycobacterial efflux pump inhibitors (EPIs). This review summarises the current state of knowledge surrounding drug-related efflux pumps in M. tuberculosis and presents recent updates within the field of mycobacterial EPIs with a view to aiding the design of an effective adjunct therapy to overcome efflux-mediated resistance in TB.
The small-molecule SMARt751 reverses resistance to ethionamide in acute and chronic mouse models of tuberculosis.
Science translational medicine
The sensitivity of , the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of , which regulates the operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with strains carrying mutations in the gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.