Compositions and methods for treating infections using cationic peptides alone or in combination with antibiotics

Abstract

Compositions and methods for treating infections, especially bacterial infections, are provided. Indolicidin peptide analogues containing at least two basic amino acids are prepared. The analogues are administered as modified peptides, preferably containing photo-oxidized solubilizer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation of allowed U.S. patent application Ser. No. 10 / 277,233 filed Oct. 18, 2002, which application claims priority from U.S. patent application Ser. No. 09 / 030,619, filed Feb. 25, 1998 and issued as U.S. Pat. No. 6,503,881, which application claims priority from U.S. Provisional Application No. 60 / 040,649, filed Mar. 10, 1997, and U.S. Provisional Application No. 60 / 060,099, filed Sep. 26, 1997, and U.S. patent application Ser. No. 09 / 030,619 is a continuation-in-part of U.S. application Ser. No. 08 / 915,314, filed Aug. 20, 1997, issued as U.S. Pat. No. 6,180,604 on Jan. 30, 2001 which claims priority from U.S. Provisional Application No. 60 / 024,754, filed Aug. 21, 1996, and U.S. Provisional Application No. 60 / 034,949, filed Jan. 13, 1997, all of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates generally to methods of treating microorganism-caused infe...

AI Technical Summary

Benefits of technology

The present invention provides a co-administration of cationic peptides with an antibiotic agent and an indolicidin analogue. The invention also provides an isolated nucleic acid molecule, expression vectors, and host cells transformed or transformed with the expression vector. The invention further provides a pharmaceutical composition comprising at least one indolicidin analogue and a physiologically acceptable buffer, optionally comprising an antibiotic agent, antiviral agent, antiparasitic agent, or antifungal agent. The invention also provides a method of treating an infection by administering a pharmaceutical composition. The invention also provides a compound modified by a conjugate of activated polyoxyalkylene and a lipophilic moiety. The modified compound can be used to treat an infection, such as a microorganism, parasite, or virus.

Problems solved by technology

However, infectious diseases are a serious concern in developing countries and in immunocompromised individuals.

In developing countries, the lack of adequate sanitation and consequent poor hygiene provide an environment that fosters bacterial, parasitic, fungal and viral infections.

Poor hygiene and nutritional deficiencies may diminish the effectiveness of natural barriers, such as skin and mucous membranes, to invasion by infectious agents or the ability of the immune system to clear the agents.

A breakdown of host defenses can also occur due to conditions such as circulatory disturbances, mechanical obstruction, fatigue, smoking, excessive drinking, genetic defects, AIDS, bone marrow transplant, cancer, and diabetes.

An increasingly prevalent problem in the world is opportunistic infections in individuals who are HIV positive.

Although vaccines may be available to protect against some of these organisms, vaccinations are not always feasible, due to factors such as inadequate delivery mechanisms and economic poverty, or effective, due to factors such as delivery too late in the infection, inability of the patient to mount an immune response to the vaccine, or evolution of the pathogen.

For other pathogenic agents, no vaccines are available.

While antibiotics have proved effective against many bacteria and thus saved countless lives, they are not a panacea.

When isolated, these peptides are toxic to a wide variety of microorganisms, including bacteria, fungi, and certain enveloped viruses.

While indolicidin acts against many pathogens, notable exceptions and varying degrees of toxicity exist.

Although cationic peptides show efficacy in vitro against a variety of pathogenic cells including gram-positive bacteria, gram-negative bacteria, and fungi, these peptides are generally toxic to mammals when injected, and therapeutic indices are usually quite small.

None of these approaches are shown to improve administration of cationic peptides.

For example, methods for the stepwise synthesis of polysorbate derivatives that can modify peptides by acylation reactions have been developed, but acylation alters the charge of a modified cationic peptide and frequently reduces or eliminates the antimicrobial activity of the compound.

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