New antimycobacterial agents in the pre-clinical phase or beyond: recent advances in patent literature (2001–2016)

ABSTRACT

Introduction: Tuberculosis, an infectious disease, has caused more deaths worldwide than any other single infectious disease, killing more than 1.5 million people each year; equating to 4,100 deaths a day. In the past 60 years, no new drugs have been added to the first line regimen, in spite of the fact that thousands of papers have been published on drugs against tuberculosis and hundreds of drugs have received patents as new potential products. Thus, there is undoubtedly an urgent need for the deployment of new effective drugs against tuberculosis.

Areas covered: This review brings to the reader the opportunity to understand the chemical and biological characteristics of all patented anti-tuberculosis drugs in North America, Europe, Japan, and Russia. The 116 patents discussed here concern new molecules in the early or advanced phase of development in the last 16 years.

Expert opinion: Of all 116 patents, only one developed drug, bedaquiline, is used, and then, only in specific cases. Another three drugs are in clinical studies. However, many other compounds, for which there are in vitro and in vivo studies, seem to fulfil the requisite criteria to be a new anti-tuberculosis agent. However, why are they not in use? Why were so many studies interrupted? Why is there no more news for many of these drugs?

KEYWORDS:

• Drug patent
• Mycobacterium tuberculosis
• tuberculosis

Article highlights

• Tuberculosis is an infectious disease that causes more deaths than any other single infectious disease worldwide, killing more than 1.5 million people each year;

• Despite substantial research and hundreds of promising compounds patented as new potential products, no new drug has been added to the first line regimen in the past 60 years;

• The long treatment period and therapeutic side effects of drugs currently in use lead to cessation of treatment and the potential for the selection of resistant mutants;

• The main mechanisms by which Mycobaterium tuberculosis (MTB) develops drug resistance are the following: 1. modifying the drug target, 2. changing the pathway that activates or metabolizes the drug, 3. reducing permeability (e.g., of efflux pumps), and 4. inactivating enzymes;

• This article covers the recent patent literature on tuberculosis drugs in the pre-clinical phase (116 in total), presenting the chemical and biological characteristics of all patented anti-tuberculosis drugs in North America, Europe, Japan, and Russia in the last 16 years;

• Of all surveyed patents, only one developed drug, bedaquiline, is used currently in tuberculosis therapy; however, its use is controversial and highly restricted. Another three substances are in the clinical phase. However, many other compounds, for which there are in vitro and in vivo studies, seem to meet the requisite criteria to be considered promising new anti-tuberculosis agents.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper has been funded by grant#2013/14957-5 São Paulo Research Foundation (FAPESP), by Coordination for the Improvement of Higher Education Personnel (CAPES) whith the Post-doctoral National Program (PNPD) and Programa de Apoio ao Desenvolvimento Científico (PADC) of School of Pharmaceutical Sciences/UNESP, Brazil.