New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects

Zumla, Alimuddin; Gillespie, Stephen H.; Höelscher, Michael; Philips, Patrick; Cole, Stewart T.; Abubakar, Ibrahim; McHugh, Timothy D.; Schito, Marco; Maeurer, Markus; Nunn, Andrew

doi:10.1016/s1473-3099(13)70328-1

Cited by 297 publications

(247 citation statements)

References 213 publications

Supporting

Mentioning

239

Contrasting

Unclassified

Order By: Relevance

“…Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs.…”

mentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

168

View full text Add to dashboard Cite

There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

show abstract

mentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

168

View full text Add to dashboard Cite

show abstract

“…Of 204 proteins, 18 have not been analysed by TuberQ as yet, one is listed as non-druggable, 16 as poorly druggable, 43 as druggable, and 126 as highly druggable. While this data has been used to develop inhibitors (23,24), no anti-TB drugs currently in clinical trials appears to have been designed from protein structural data (25,26). Instead, drugs were mainly discovered through phenotypic screening of bacteria cells exposed to various compounds (27).…”

Section: Functional Categorization and Druggability Of Mtb H37rv Crysmentioning

confidence: 99%

Assessing the progress of Mycobacterium tuberculosis H37Rv structural genomics

et al. 2015

View full text Add to dashboard Cite

Tuberculosis threatens human health nowhere more than in developing countries with large malnourished and/or immune-compromised (e.g. HIV infected) populations. The etiological agent, Mycobacterium tuberculosis (Mtb), is highly infectious and current interventions demonstrate limited ability to control the epidemic in particular of drug resistant Mtb strains. New drugs and vaccines are thus urgently required. Structural biologists are critical to the TB research community. By identifying potential drug targets and solving their three dimensional structures they open new avenues of identifying potential inhibitors complementing the screening of novel compounds and the investigation of Mtb's molecular physiology by pharmaceutical companies and academic researchers. Much effort has gone into structurally elucidating the Mtb proteome though much remains to be done with progress primarily limited by technological constraints. We review the currently available data for Mtb H37Rv to extract the lessons they have taught us. KeywordsMycobacterium tuberculosis, structural genomics, drug target AbbreviationsAll abbreviations in the manuscript are standard in the field.

show abstract

“…Experiences with implementing DOTS and our extensive knowledge of the biosocial and structural drivers of incidence and resistance tell us that a multilayered approach is necessary. Even as TB remains a disease of social disadvantage and deprivation, developing an effective armamentarium remains a pre-condition of sustainable progress in the fight against MDR-TB, especially in resource-poor and endemic settings (Zumla et al 2014;Dheda et al 2014). …”

Section: The Innovation Gap and The Logic Of Market Incentivesmentioning

confidence: 99%

“…Public-private partnerships such as the Global TB Alliance, the Critical Path to TB Drug Regimens Initiative and The Gates Foundation-funded TB Drug Accelerator have had some success in bringing new drugs/agents to market (Zumla et al 2014). The TB Alliance funded the development of Bedaquiline, which was approved by the FDA in December 2012 (the first novel drug since Rifampacin 1967).…”

Section: Attempts To Boost Innovationmentioning

confidence: 99%

“…Leading experts point to recent progress in developing new agents, but agree that further effort is needed (Dheda et al 2014;Zumla et al 2014;Abubakar et al 2013). We believe that this is where bioethics comes in, because it can offer important perspectives that are not tied to a particular solution and help us to keep what is ethically important in focus-promoting global equity by reducing poverty, optimising public health and preventing the spread of disease.…”

Section: Reformulating the Problemmentioning

confidence: 99%

See 1 more Smart Citation

The Political and Ethical Challenge of Multi-Drug Resistant Tuberculosis

et al. 2015

View full text Add to dashboard Cite

This article critically examines current responses to multi-drug resistant tuberculosis and argues that bioethics needs to be willing to engage in a more radical critique of the problem than is currently offered. In particular, we need to focus not simply on market-driven models of innovation and anti-microbial solutions to emergent and re-emergent infections such as TB. The global community also needs to address poverty and the structural factors that entrench inequalities-thus moving beyond the orthodox medical/public health frame of reference. The problem of drug-resistant tuberculosisTwenty years after tuberculosis (TB) was declared a global public health emergency, it remains a leading infectious cause of death worldwide. TB also remains primarily a disease of poverty; higher rates of incidence follow in lock step with social and economic disadvantage. Two billion people are known to be infected with Mycobacterium tuberculosis. In its most recent report, The World Health Organization (2012) estimated that 8.6 million people develop TB each year and 1.3 million people die from active infection -the vast majority amongst the poor and marginalized in low-and middle-income countries.Data from surveillance programs and drug resistance surveys suggests that almost 4 percent of newly diagnosed cases and 20 percent of re-activated infections are caused by multi-drug resistant strains [MDR-TB] of the bacterium. About 630,000 (roughly 10 percent) of these MDR-TB cases exhibit extensive drug resistance [XDR-TB], which means that at least one of the two most potent first-line TB medications

show abstract

New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects

Cited by 297 publications

References 213 publications

Antiinfectives targeting enzymes and the proton motive force

Antiinfectives targeting enzymes and the proton motive force

Assessing the progress of Mycobacterium tuberculosis H37Rv structural genomics

The Political and Ethical Challenge of Multi-Drug Resistant Tuberculosis

Contact Info

Product

Resources

About