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Overcoming intrinsic multidrug resistance to discover and expand the repertorie of antibiotics active against mycobacterialpathogens

Applicant Grzesiek Stephan
Number 69384
Funding scheme NRP 49 Antibiotic resistance
Research institution Abteilung Mikrobiologie Biozentrum Universität Basel
Institution of higher education University of Basel - BS
Main discipline Infectious Diseases
Start/End 01.10.2002 - 31.03.2006
Approved amount 293'892.00
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Lay Summary (English)

Lead
Lay summary
Overcoming intrinsic multidrug resistance to discover and expand the repertoire of antibiotics active against mycobacterial pathogens

Mycobacterial infections are one of the leading causes of human mortality, resulting from tuberculosis (TB), opportunistic infections of AIDS patients and leprosy. Chemotherapeutic options are limited and compromised by the intrinsic antibiotic resistance of these bacteria. Our proposal initiates an ambitious program for the discovery and design of novel antimycobacterial drugs.

Background
Mycobacteria have been a menace to human health throughout history. Mycobacterium tuberculosis, the etiological agent of TB, is presently one of the greatest infectious agents of mortality worldwide, killing nearly three million people annually. Pathogenic mycobacteria cause other important human diseases such as leprosy and the opportunistic infections of AIDS patients. A deadly synergy with the human immunodeficiency virus (HIV) and the emergence of multidrug resistant strains have reaffirmed mycobacteria as a primary public health threat throughout the world. Chemotherapy for this slow growing intracellular pathogen is complex and protracted (at least 6 months) since M. tuberculosis is intrinsically resistant to most previously discovered, readily available antibiotics. It can persist in an antibiotic resistant state and be reactivated decades later in some patients. This antibiotic resistant trait has traditionally been attributed to its waxy, impenetrable cell envelope. We have shown that intrinsic resistance is in fact more complex, involving the participation of other effectors within the cell, and discovered that a broad spectrum of multidrug resistance in Mycobacterium species depends on a single gene (Whm). In addition to its essential role in drug resistance, Whm belongs to a family of M. tuberculosis proteins that have essential roles for viability and are implicated in maintaining long-term persistence.

Aim
We would like to define the structure of Whm and its function in conferring multidrug resistance using a variety of
microbiological, biochemical and biophysical approaches. Studies of antibiotic resistance in other bacteria suggest that
underlying mechanisms may include antibiotic exclusion, modification of the antibiotic, or modification of its target. We aim to identify these resistance genes and understand how Whm activates their expression. The three dimensional structure of Whm will allow us to understand how it works and rationally design drugs that inhibit its activity. In addition to making strains antibiotic sensitive, we hope that drugs against Whm proteins may also inhibit growth or kill persistent bacteria.

Significance
In summary, we hope to identify a single compound that can simultaneously target all of the Whm-like proteins needed for viability, persistence, and intrinsic drug resistance. These studies could lead to the discovery of inhibitors of Whm having important clinical implications worldwide. A Whm inhibitory compound might:
1) Reduce the drug resistance of mycobacteria causing tuberculosis, leprosy, and lethal complications in AIDS patients. The concept of administering inhibitors of Whm for use in combination with the frontline anti-mycobacterial antibiotics may improve on their efficacy.
2) Provide novel antibiotics and allow mobilization of a wide variety of readily available drugs of proven clinical efficacy against other bacteria for use against mycobacteria.
3) Shorten the problematic duration of treatment of active and persistent infections.


Direct link to Lay Summary Last update: 21.02.2013

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