sq-109 and Tuberculosis

Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good

Topics: Antitubercular Agents; COVID-19 Drug Treatment; Drug Discovery; Humans; Mycobacterium tuberculosis; Tuberculosis

Tuberculosis (TB) continues to claim the lives of around 1.7 million people per year. Most concerning are the reports of multidrug drug resistance. Paradoxically, this global health pandemic is demanding new therapies when resources and interest are waning. However, continued tuberculosis drug discovery is critical to address the global health need and burgeoning multidrug resistance. Many diverse classes of antitubercular compounds have been identified with activity in vitro and in vivo. Our analyses of over 100 active leads are representative of thousands of active compounds generated over the past decade, suggests that they come from few chemical classes or natural product sources. We are therefore repeatedly identifying compounds that are similar to those that preceded them. Our molecule-centered cheminformatics analyses point to the need to dramatically increase the diversity of chemical libraries tested and get outside of the historic

Topics: Antitubercular Agents; Bacterial Proteins; Drug Discovery; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Nucleoside-Phosphate Kinase; Structure-Activity Relationship; Tuberculosis

Despite enormous efforts have been made in the hunt for new drugs, tuberculosis (TB) still remains the first bacterial cause of mortality worldwide, causing an estimated 8.6 million new cases and 1.3 million deaths in 2012. Multi-drug resistant-TB strains no longer respond to first-line drugs and are inexorably spreading with an estimated 650,000 cases as well as extensively-drug resistant-TB strains, which are resistant to any fluoroquinolone and at least one of the second-line drugs, with 60,000 cases. Thus the discovery and development of new medicines is a major keystone for tuberculosis treatment and control. After decades of dormancy in the field of TB drug development, recent efforts from various groups have generated a promising TB drug pipeline. Several new therapeutic agents are concurrently studied in clinical trials together with much activity in the hittolead and lead optimization stages. In this article we will review the recent advances in TB drug discovery with a special focus on structure activity relationship studies of the most advanced compound classes.

Topics: Animals; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis; Tuberculosis, Multidrug-Resistant

Recent advances in the development of new drugs and regimens provide hope that well tolerated, effective, and shorter-duration treatments for tuberculosis (TB) will become available. This review covers the recent trials of new TB drugs and regimens.. Moxifloxacin and levofloxacin have equally good efficacy and safety in the early phase of treatment of multidrug-resistant TB (MDR-TB), and linezolid has the potential to cure refractory cases of MDR-TB. Bedaquiline and delamanid may be the best drug candidates for enhancing treatment options for MDR-TB. New chemicals, such as sutezolid, AZD5847, PA-824, SQ109, and BTZ043, show potent activity against Mycobacterium tuberculosis. Late-generation fluoroquinolones in combination with the first-line and second-line anti-TB drugs have been used to shorten the treatment duration in drug-susceptible and MDR-TB.. New drugs and new combination regimens in clinical trials are expected to increase therapeutic efficacy and shorten treatment duration in both drug-susceptible and drug-resistant TB.

Topics: Acetamides; Adamantane; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Administration Schedule; Drug Design; Ethylenediamines; Female; Fluoroquinolones; Humans; Levofloxacin; Linezolid; Male; Moxifloxacin; Nitroimidazoles; Oxazoles; Oxazolidinones; Spiro Compounds; Thiazines; Tuberculosis; Tuberculosis, Multidrug-Resistant

Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60's of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis.

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Drug Discovery; Humans; Tuberculosis

Existing drugs have limited efficacy against the rising threat of drug-resistant TB, have significant side effects, and must be given in combinations of four to six drugs for at least 6 months for drug-sensitive TB and up to 24 months for drug-resistant TB. The long treatment duration has led to increased patient noncompliance with therapy. This, in turn, drives the development of additional drug resistance in a spiral that has resulted in some forms of TB being currently untreatable by existing drugs. New antitubercular drugs in development, particularly those with mechanisms of action that are different from existing first- and second-line TB drugs, are anticipated to be effective against both drug-sensitive and drug-resistant TB. SQ109 is a new TB drug candidate with a novel mechanism of action that was safe and well tolerated in Phase I and early Phase II clinical trials. We describe herein the identification, development and characterization of SQ109 as a promising new antitubercular drug.

Topics: Adamantane; Animals; Antitubercular Agents; Drug Discovery; Drug Interactions; Drug Resistance, Multiple, Bacterial; Ethylenediamines; Humans; Mice; Mycobacterium tuberculosis; Tuberculosis

Tuberculosis (TB) drug research and development efforts have resurged in the past 10 years to meet urgent medical needs, but enormous challenges remain. These urgent needs are largely driven by the current long and arduous multidrug regimens, which have significant safety, tolerability and compliance issues; rising and disturbing rates of multidrug- and extensively drug-resistant TB; the existence of approximately 2 billion individuals already latently infected with Mycobacterium tuberculosis, the causative pathogen of TB; and a global TB-HIV co-epidemic. Stakeholders in TB drug development are moving to enable and streamline development and registration of novel, multidrug treatment regimens, comprised of multiple new chemical entities with novel mechanisms of action that do not demonstrate cross-resistance to current first- and second-line TB drugs. Ideally, these new regimens will ultimately provide a short, simple treatment suitable for essentially all TB patients, whether sensitive or resistant to the current anti-TB agents, whether HIV-positive or -negative, and irrespective of patient age. This article reviews the challenges faced by those trying to develop these novel regimens and the key agents currently in clinical testing for TB; the latter are organized for discussion into three categories: (i) novel drugs (TMC207, SQ109, sudoterb [LL3858]); (ii) present first-line TB drugs being re-evaluated to optimize their efficacy (rifampicin, rifapentine); and (iii) currently licensed drugs for other indications and 'next-generation' compounds of the same chemical class being repurposed for TB (gatifloxacin and moxifloxacin; linezolid, PNU100480 and AZD5847; metronidazole, OPC-67683 and PA-824).

Topics: Adamantane; Antitubercular Agents; Diarylquinolines; Drug Discovery; Ethylenediamines; Humans; Quinolines; Tuberculosis

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Mycobacterium tuberculosis; Rifamycins; Tuberculosis

Topics: Adamantane; Animals; Antitubercular Agents; Ethylenediamines; Humans; Treatment Outcome; Tuberculosis

Novel chemotherapeutic drugs are needed to improve tuberculosis (TB) control, especially in the developing world. Given the magnitude of the problem and the resources available in countries that have the highest burden of disease, the present standards of care for the treatment of drug-susceptible TB, drug-resistant TB, TB/human immunodeficiency virus (HIV) coinfection, and latent TB infection are all unsatisfactory. Because no truly novel compounds for the treatment of TB have been discovered in the past 40 years, the recent enhanced activity in the research and development of new TB drugs is extremely encouraging. Seven compounds are presently in clinical development specifically for the treatment of TB. Other known antibiotic compound families are being investigated preclinically, in an attempt to identify new antimicrobial drugs with specific antituberculous activity. In addition, novel targets have been identified and are the subject of efforts to validate their potential usefulness in the treatment of TB.

Topics: Adamantane; Animals; Antitubercular Agents; Clinical Trials as Topic; Diamines; Diarylquinolines; Ethylenediamines; Fluoroquinolones; Humans; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Quinolines; Tuberculosis

We tested a series of SQ109 analogues against

Topics: Antitubercular Agents; Diphosphates; Humans; Mycobacterium smegmatis; Mycobacterium tuberculosis; Tuberculosis

Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.

Topics: Adamantane; Antitubercular Agents; Bacterial Proteins; Biological Transport; Drug Delivery Systems; Drug Design; Ethylenediamines; Humans; Membrane Proteins; Membrane Transport Proteins; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenylurea Compounds; Rimonabant; Tuberculosis

As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis.

Topics: Adamantane; Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Combinations; Ethylenediamines; Humans; Lung; Mice; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis

The aim of the present investigation was to develop matrix tablet formulations for the

Topics: Adamantane; Administration, Oral; Antitubercular Agents; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Compounding; Drug Liberation; Ethers; Ethylenediamines; Excipients; Hydrogen-Ion Concentration; Solubility; Tablets; Tuberculosis

We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosynthesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.

Topics: Anti-Infective Agents; Antineoplastic Agents; Antitubercular Agents; Bacteria; Breast Neoplasms; Cell Proliferation; Drug Design; Drug Discovery; Female; Fungi; Humans; Malaria, Falciparum; MCF-7 Cells; Membrane Transport Proteins; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Plasmodium falciparum; Structure-Activity Relationship; Tuberculosis; Tumor Cells, Cultured

Substitution of the new diamine antibiotic SQ109 for ethambutol in a mouse model of chronic tuberculosis (TB) improved efficacy of combination drug therapy with first-line TB drugs rifampin and isoniazid, with or without pyrazinamide: at 8 weeks, lung bacteria were 1.5 log10 lower in SQ109-containing regimens.

Topics: Adamantane; Animal Experimentation; Animals; Anti-Bacterial Agents; Antitubercular Agents; Drug Therapy, Combination; Ethylenediamines; Lung; Mice; Mycobacterium tuberculosis; Treatment Outcome; Tuberculosis