Targeting Bacterial Virulence for a New Class of Infection Control

Introduction

The rise of antibiotic-resistant bacteria has created a significant global health challenge, one that threatens the effectiveness of existing treatments and puts millions of lives at risk. While traditional antibiotics aim to kill or inhibit the growth of bacteria, this approach has led to the development of resistant strains, diminishing the efficacy of available drugs. Our patented method offers a breakthrough alternative—by targeting and reducing bacterial virulence, it offers a novel strategy to combat infections without driving resistance.

The Global Need for Alternatives to Traditional Antibiotics

The overuse and misuse of antibiotics have accelerated the development of drug-resistant bacteria, commonly referred to as “superbugs.” These resistant strains are increasingly difficult to treat, leading to prolonged illnesses, higher healthcare costs, and increased mortality rates. Existing antibiotics often come with side effects, and their efficacy is rapidly diminishing as resistance spreads.

Traditional antibiotic therapies focus on killing bacteria or inhibiting their growth, which places selective pressure on bacterial populations and contributes to the development of resistance. There is a growing need for novel therapies that can effectively treat infections while reducing the likelihood of resistance development.

A Novel Approach: Reducing Bacterial Virulence

Our patented technology introduces an innovative approach by targeting bacterial virulence factors—molecules that enable bacteria to infect and damage host tissues. Instead of killing the bacteria outright, this method reduces their ability to cause disease, disarming the pathogens and allowing the immune system to clear the infection more effectively. By focusing on virulence rather than bacterial survival, this approach minimizes the selective pressure that leads to resistance.

This method holds promise for treating a wide range of bacterial infections, particularly those caused by antibiotic-resistant strains. By reducing virulence, bacteria are less able to evade the immune system, making them more susceptible to treatment. This strategy also offers the potential for fewer side effects, as it spares beneficial bacteria that are often killed by broad-spectrum antibiotics.

Key Benefits of This Approach

Reduced Resistance Development: By targeting virulence factors instead of bacterial survival, this method avoids the selective pressure that drives antibiotic resistance.
Effective Against Resistant Strains: This approach is particularly valuable in treating infections caused by antibiotic-resistant bacteria, where traditional therapies may fail.
Fewer Side Effects: This method spares the body’s beneficial bacteria, reducing the disruption to the microbiome often caused by traditional antibiotics.
Broad Applications: Applicable to a wide range of bacterial infections, from common ailments to severe, drug-resistant infections.

A Strategic Shift in Infection Control

Licensing this method for reducing bacterial virulence offers pharmaceutical companies and healthcare providers an opportunity to lead in the next generation of antibacterial therapies. With its potential to combat antibiotic resistance and provide more effective treatments, this technology represents a vital tool in the ongoing battle against bacterial infections.

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Abstract
Claims

A method of reducing virulence in a bacterium comprising at least one of a GacS/GacA-type system, a HrpX/HrpY-type system, a T3SS-type system, and a Rsm-type system, the method comprising contacting the bacterium with an effective amount of a compound described herein.

1. A method of reducing virulence in a bacterium comprising at least one of a GacS/GacA-type system, a HrpX/HrpY-type system, a T3SS-type system, and a Rsm-type system, the method comprising contacting the bacterium with an effective amount of a compound of formula (III):

wherein:

A is aryl or heteroaryl;

R₁is selected from oxygen, sulfur and a bond;

n is 0, 1, 2, 3, 4 or 5;

each R₂is independently selected from alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, alkoxy, sulfhydryl, thioether, sulfo, silyl, phosphono, halo, carboxy, nitro, amino, formyl, aryl, haloalkyl, ester, amido and heterocyclyl groups; and

R₇is selected from hydroxy, hydroxyalkyl, alkoxy, carboxy, hydroxamic acid, hydrazide, hydrazinocarbonyl, aryl, ester, amino, amido, thioamido, sulfonyl, sulfinic acid, sulfonic acid, sulfinate, sulfonate, phosphonic acid, phosphonate, and substituted or unsubstituted bicyclic heteroaromatic groups;

or a salt thereof.

2.-7. (canceled)

8. A method of reducing virulence in a bacterium comprising at least one of a GacS/GacA-type system, a HrpX/HrpY-type system, a T3SS-type system, and a Rsm-type system, the method comprising contacting the bacterium with an effective amount of a compound of formula (IV):

wherein:

A is aryl or heteroaryl;

R₁is selected from alkylene, heteroalkylene, oxygen, sulfur and a bond;

n is 0, 1, 2, 3, 4 or 5;

R₇is selected from hydroxamic acid, hydrazide, hydrazinocarbonyl, aryl, amino, amido, thioamido, sulfonyl, sulfinic acid, sulfonic acid, sulfinate, sulfonate, phosphonic acid, phosphonate, and substituted or unsubstituted bicyclic heteroaromatic groups;

or a salt thereof.

9.-15. (canceled)

16. A method of reducing virulence in a bacterium comprising at least one of a GacS/GacA-type system, a HrpX/HrpY-type system, a T3SS-type system, and a Rsm-type system, the method comprising contacting the bacterium with an effective amount of a compound of formula (V):

wherein:

A is aryl or heteroaryl;

R₁is selected from alkylene, heteroalkylene, oxygen, sulfur and a bond;

n is 1, 2, 3, 4 or 5;

each R₂is independently selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, sulfhydryl, thioether, sulfo, silyl, phosphono, fluoro, bromo, iodo, carboxy, nitro, amino, formyl, aryl, haloalkyl, ester, amido and heterocyclyl groups; and

or a salt thereof.

17.-21. (canceled)

22. A method of reducing virulence in a bacterium comprising at least one of a GacS/GacA-type system, a HrpX/HrpY-type system, a T3SS-type system, and a Rsm-type system, the method comprising contacting the bacterium with an effective amount of a compound of formula (VI):

wherein:

A is selected from imidazole, thiophene, furan, oxazole, thiazole, quinoline, benzofuran, benzothiofuran and carbazole;

R₁is selected from alkylene, heteroalkylene, oxygen, sulfur and a bond;

n is 0, 1, 2, 3, 4 or 5;

or a salt thereof.

23.-25. (canceled)

26. A method of reducing virulence in a bacterium comprising at least one of a GacS/GacA-type system, a HrpX/HrpY-type system, a T3SS-type system, and a Rsm-type system, the method comprising contacting the bacterium with an effective amount of a compound of formula (VII):

wherein:

A is aryl or heteroaryl;

R₁is selected from alkylene, heteroalkylene, oxygen, sulfur and a bond;

n is 2, 3, 4 or 5;

or a salt thereof.

27.-31. (canceled)

32. A method of reducing virulence in a bacterium comprising at least one of a GacS/GacA-type system, a HrpX/HrpY-type system, a T3SS-type system, and a Rsm-type system, the method comprising contacting the bacterium with an effective amount of a compound selected from the group consisting of:

or a salt thereof.

33.-34. (canceled)

35. The method of claim 1, wherein the bacterium is of a bacterial genus selected from the group consisting of Pseudomonas, Dickeya, Erwinia, Azotobacter, Vibrio, Yersinia, Pectobacterium, Salmonella, Chlamydia, Xanthomonas, Ralstonia, Shewanella, Shigella and Escherichia.

36. The method of claim 1, wherein the bacterium is a Pseudomonas spp. selected from the group consisting of P. aureofaciens, P. chlororaphis, P. fluorescens, P. marginalis, P. syringae, P. tolaasii, P. viridiflava, and P. aeruginosa.

37. The method of claim 36, wherein the bacterium is P. aeruginosa.

38. The method of claim 1, wherein the bacterium is an Erwinia-related strain selected from the group consisting of Dickeya dadantii, Pectobacterium carotovora, Pectobacterium atroseptica, and Erwinia amylovora.

39. The method of claim 1, wherein the bacterium is a Salmonella spp. selected from the group consisting of S. typhimurium and S. enterica.

40. The method of claim 1, wherein the bacterium is Ralstonia solanacearum.

41. The method of claim 1, wherein the bacterium is a Xanthomonas spp. selected from the group consisting of X. campestris, X. axonopodis and X. oryzae.

42. The method of claim 1, wherein the bacterium is associated with a subject, and wherein the bacterium is contacted with the compound by administering the compound to the subject.

43. The method of claim 42, wherein the subject is a plant.

44.-46. (canceled)

47. The method of claim 43, wherein the composition is administered to at least one of leaves, stems, roots, buds, fruits, frill, stump, bark, roots, soil or rhisozphere.

48. (canceled)

49. The method of claim 43, wherein the composition is sprayed on the plant.

50. The method of claim 42, wherein the subject is an animal.

51.-54. (canceled)

55. The method of claim 1, wherein the bacterium is on a surface, and wherein the bacterium is contacted with the compound by contacting the surface with the compound.

56. (canceled)

57. A compound selected from the group consisting of: