Novel antibiotics / antipersister molecules

Research carried out by Evelien Gerits, Valerie Defraine, Taiyeb Zahir, Natalie Verstraeten, Maarten Fauvart

Pseudomonas aeruginosa infections are extremely difficult to treat with currently available antibacterials. This is primarily due to significant intrinsic resistance, caused by low permeability of the outer cell membrane. In addition, P. aeruginosa has an extraordinary ability to develop resistance to virtually any antibiotic to which it is exposed, and multiple resistance mechanisms can be present concurrently. This has led to rapidly rising rates of (multi)drug resistance.

Because increased resistance is usually not correlated with decreased virulence in P. aeruginosa, mortality rates are on the rise as well. Evidently, there is a pressing need for the development of new antipseudomonal agents.

Infections caused by P. aeruginosa are often associated with the formation of biofilms.

These microbial communities are highly recalcitrant to antibiotic treatments.

Recent findings point to a small fraction of specialized cells within the biofilm as the main explanation for biofilm tolerance and, more importantly, as the major culprit for treatment failure of P. aeruginosa biofilm-associated infections.

These cells, termed persisters, are dormant cells that are highly tolerant to antibiotics, residing within an otherwise sensitive population. In the absence of antibiotics, persister cells resuscitate and repopulate the biofilm, resulting in a relapse of infection.

A treatment targeted specifically at persisters, either directly killing them or restoring antibiotic sensitivity, is likely an essential part of any therapy aiming to achieve complete eradication of a P. aeruginosa infection (Fauvart et al., 2011).

High resistance rates have severely limited the treatment options available to clinicians fighting P. aeruginosa infections, and toxic antibiotics such as polymyxins are increasingly the only remaining alternative. However, to date, no drugs in clinical development address the issue of resistance. Moreover, the presence of antibiotic-tolerant persister cells frequently renders the application of antibiotics ineffective even in the absence of drug resistance, consequently leading to recurring infections and chronic disease.

No persister-specific therapies are currently commercially available.

Driven by the clear, unmet need for new therapies for P. aeruginosa infections, we have initiated a research effort to contribute to the development of novel approaches to antipseudomonal drug therapy. We believe that specifically focusing on bacterial persistence will be key to forcing a breakthrough in the battle against chronic infections.

Part of this research is carried out as partner in the COATIM consortium, funded by the EU 7th framework program (FP7).

Scanning electron microscopy image of bacteria on a surface. Credit: Maarten Fauvart and MTM, KU Leuven.

Related publications:

Defraine V., Schuermans J., Grymonprez B., Govers S.K., Aertsen A., Fauvart M., Michiels J., Lavigne R., Briers Y. (2016) Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii . Antimicrob Agents Chemother. 23:3480-3488 -- PubMed -- PDF

Gerits E., Kucharíková S., Van Dijck P., Erdtmann M., Krona A., Lövenklev M., Fröhlich M., Dovgan B., Impellizzeri F., Braem A., Vleugels J., Robijns S.C., Steenackers H.P., Vanderleyden J., De Brucker K., Thevissen K., Cammue B.P., Fauvart M., Verstraeten N., Michiels J. (2016) Antibacterial activity of a new broad-spectrum antibiotic covalently bound to titanium surfaces. J. Orthop. Res. doi:10.1002/jor.23238 -- PubMed -- PDF

Gerits E., Blommaert E., Lippell A., O'Neill A.J., Weytjens B., De Maeyer D., Fierro A.C., Marchal K., Marchand A., Chaltin P., Spincemaille P., De Brucker K., Thevissen K., Cammue B.P., Swings T., Liebens V., Fauvart M., Verstraeten N., Michiels J. (2016) Elucidation of the Mode of Action of a New Antibacterial Compound Active against Staphylococcus aureus and Pseudomonas aeruginosa. PLoS One 11(5):e0155139 -- PubMed -- PDF

Liebens V., Gerits E., Knapen W.J., Swings T., Beullens S., Steenackers H.P., Robijns S., Lippell A., O'Neill A.J., Veber M., Froehlich M., Krona A., Loevenklev M., Corbau R., Marchand A., Chaltin P., De Brucker K., Thevissen K., Cammue B.P., Fauvart M., Verstraeten N., Michiels J. (2014) Identification and characterization of an anti-pseudomonal dichlorocarbazol derivative displaying anti-biofilm activity. Bioorg. Med. Chem. Lett. 24(23):5404-5408 -- PubMed -- PDF

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