Modulation of pathogenicity

Abstract

The present invention relates to the use of compounds of the general Formula (I):wherein in Formula (I),R is H, alkyl, cycloalkyl, aryl or heteroaryl;R1 is H, alkyl, cycloalkyl, aryl or heteroaryl;R2 is H, alkyl, cycloalkyl, aryl or heteroaryl;A1 and A2 each independently represent an optionally substituted C1-C20-alkyl group which may contain one or more group(s) Z, or a monocyclic or polycyclic optionally substituted aromatic or non-aromatic ring system which may contain one or more group(s) X, and in case of a polycyclic ring system, said system contains at least one aromatic ring;Z is selected from the group consisting of S, O, N, NR4, CO, CO2, CS, SO or SO2 X is selected from the group consisting of S, O, N; NR4, SO or SO2;

Description

STATEMENT OF RELATED APPLICATIONS[0001]The present application is a divisional of co-pending application Ser. No. 10 / 429,875, filed May 6, 2003, which is a continuation-in-part of application Ser. No. 10 / 094,301, filed Mar. 8, 2002, now abandoned, the contents of each are herein incorporated by reference in their entirety.BACKGROUND OF THE INVENTION[0002]The present invention relates to the use of compounds such as amide, carbazide and hydrazide derivatives as selective inhibitors of bacterial pathogens. In particular the invention refers to a family of compounds that block the quorum sensing system of Gram-negative bacteria, a process for their manufacture, pharmaceutical compositions containing them and to their use for the treatment and prevention of microbial damages and diseases, in particular for diseases where there is an advantage in inhibiting quorum sensing regulated phenotypes of pathogens.[0003]Many microorganisms, including bacteria, fungi, protozoa and algae cause seve...

AI Technical Summary

Benefits of technology

[0019]Accordingly, we have been able to find compounds that can significantly reduce virulence gene expression and biofilm formation of several human pathogens. In contrast to the furanones the compounds of this invention do not show any toxic effect and are therefore suitable for applications in a wide area. Such applications could be the use of the compounds for instance as new antibiotic therapeutics, disinfectants, antifouling coatings or coatings of medical devices. In contrast to traditional antibacterial agents (like amide or 1,2-acylhydrazine derivatives in WO 01 / 51456; for the synthesis of amide or 1,2-acylhydrazine derivatives see also EP 638545 and EP 982292), the compounds of the present invention do not kill the microorganisms, but render them avirulent. The advantage of this alternative strategy is that the emergence of bacterial resistance against such antimicrobials is extremely improbable.

[0020]In general, the present invention provides compounds selectively modulating bacterial cell-cell communication. Through inhibition of this communication system the expression of many HSL-dependent virulence genes and other phenotypes like swarming motility and biofilm formation are significantly reduced or completely abolished rendering a bacterial population more susceptible to the host immune-response or to treatment with traditional antibacterial agents.

Problems solved by technology

Many microorganisms, including bacteria, fungi, protozoa and algae cause severe damages or diseases in different areas such as industry, agriculture, environment and medicine Especially bacteria as human pathogens cause tremendous costs in public health systems worldwide.

The latter approach has, however, lacked specific targets for rational drug design.

Biofilms represent a severe problem as bacteria integrated in such a polymer matrix develop resistance to conventional antimicrobial agents.

Furthermore, microbial biofilms growing for example on ship hulls increase fuel consumption through enhanced frictional resistance and simultaneously reduce maneuverability.

Since biofilm formation of both organisms is demonstrated to require an HSL signaling system, inhibition of their quorum sensing systems would result in an impaired ability to form biofilms and therefore in an increased susceptability to antibacterial treatment.

Beside the role of HSL derivatives as signaling molecules of bacterial cell-to-cell communication it has been demonstrated that HSL interfere also with higher organisms.

However, none of these compounds have been developed as antimicrobial agents, e.g. in medical therapy, so far.

However, the use of most of these furanone compounds is limited due to their toxicity making them unsuitable for veterinary and medical applications.

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