sq-109 and Tuberculosis--Multidrug-Resistant

Tuberculosis (TB) being the leading infectious killer in the domain wherein globally, almost 20% of all TB strains are resistant to at least 1 major TB drug and there's a growing incidence of multi-drug resistance tuberculosis (MDR-TB). Looking at the current scenario and challenges the existing strategies fall back in terms of treatment of TB. So, to overcome this new, stronger, improved TB drug pipeline and a new standard for the development of novel anti-TB drugs are required in order to make more drug-resistant and efficient drug which also lower the duration period of the treatment of the TB. This review article aims to highlight the recent developments in the anti-tuberculosis agents, those are currently in the clinical development stage.

Topics: Adamantane; Antitubercular Agents; Diarylquinolines; Drug Development; Drug Therapy, Combination; Duration of Therapy; Ethambutol; Ethylenediamines; Humans; Isoniazid; Macrolides; Medication Adherence; Nitroimidazoles; Oxazolidinones; Pyrazinamide; Rifampin; Tuberculosis, Multidrug-Resistant

The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens.

Topics: Adamantane; Antitubercular Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diarylquinolines; Drug Therapy, Combination; Ethylenediamines; Extensively Drug-Resistant Tuberculosis; Female; Follow-Up Studies; Humans; Male; Nitroimidazoles; Oxazoles; Oxazolidinones; Treatment Outcome; Tuberculosis, Multidrug-Resistant

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

The current 6-month tuberculosis (TB) therapy is suboptimal with significant side effects and a poor patient compliance problem that frequently selects drug-resistant organisms. The increasing drug-resistant TB problem highlights the need to develop new and more effective drugs. Significant progress has been made recently with several new drug candidates currently in clinical trials. Improved understanding of persister biology and development of persister drugs are likely to be important for developing a more effective therapy.

Topics: Adamantane; AIDS-Related Opportunistic Infections; Animals; Anti-Bacterial Agents; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Drugs, Investigational; Ethylenediamines; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Humans; Isoniazid; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifampin; Treatment Refusal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

MmpL3, a resistance-nodulation-division (RND) superfamily transporter, has been implicated in the formation of the outer membrane of Mycobacterium tuberculosis; specifically, MmpL3 is required for the export of mycolic acids in the form of trehalose monomycolates (TMM) to the periplasmic space or outer membrane of M. tuberculosis. Recently, seven series of inhibitors identified by whole-cell screening against M. tuberculosis, including the antituberculosis drug candidate SQ109, were shown to abolish MmpL3-mediated TMM export. However, this mode of action was brought into question by the broad-spectrum activities of some of these inhibitors against a variety of bacterial and fungal pathogens that do not synthesize mycolic acids. This observation, coupled with the ability of three of these classes of inhibitors to kill nonreplicating M. tuberculosis bacilli, led us to investigate alternative mechanisms of action. Our results indicate that the inhibitory effects of adamantyl ureas, indolecarboxamides, tetrahydropyrazolopyrimidines, and the 1,5-diarylpyrrole BM212 on the transport activity of MmpL3 in actively replicating M. tuberculosis bacilli are, like that of SQ109, most likely due to their ability to dissipate the transmembrane electrochemical proton gradient. In addition to providing novel insights into the modes of action of compounds reported to inhibit MmpL3, our results provide the first explanation for the large number of pharmacophores that apparently target this essential inner membrane transporter.

Topics: Adamantane; Anti-Bacterial Agents; Antitubercular Agents; Bacterial Proteins; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carrier Proteins; Cell Membrane; Cord Factors; Drug Resistance, Multiple, Bacterial; Ethylenediamines; Membrane Proteins; Membrane Transport Proteins; Microbial Sensitivity Tests; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycolic Acids; Phenylurea Compounds; Piperazines; Proton Ionophores; Pyrroles; Tuberculosis, Multidrug-Resistant; Valinomycin; Vitamin K 2