The present invention relates to novel antimicrobial agents and, more particularly, to a novel class of polymers which are designed to exert antimicrobial activity while being stable, non-toxic and avoiding development of resistance thereto. The present invention further relates to pharmaceutical compositions, medical devices and food preservatives containing such polymers and to methods of treating medical conditions associated with pathogenic microorganisms utilizing same.
Antibiotics, which are also referred to herein and in the art as antibacterial or antimicrobial agents, are natural substances of relatively small size in molecular terms, which are typically released by bacteria or fungi. These natural substances, as well as derivatives and/or modifications thereof, are used for many years as medications for treating infections caused by bacteria.
The advancements in the field of antimicrobial agents in general, and antibiotics in particular had transformed medical care and dramatically reduced illness and death from infectious diseases. However, over the decades, almost all the prominent infection-causing bacterial strains have developed resistance to antibiotics.
Antibiotic resistance can result in severe adverse outcomes, such as increased mortality, morbidity and medical care costs for patients suffering from common infections, once easily treatable with antibiotics [1-6] and therefore became one of the most recognized clinical problems of today's governmental, medicinal and pharmaceutical research (U.S. Congress, Office of Technology Assessment, Impacts of Antibiotic-Resistant Bacteria, OTA-H-629, Washington, D.C., U.S. Government Printing Office (1995); House of Lords, Science and Technology 7th Report: Resistance to Antibiotics and Other Antimicrobial Agents, HL Paper 81-II, session (1997-98); and Interagency Task Force on Antimicrobial Resistance, A Public Health Action Plan to Combat Antimicrobial Resistance. Part 1: Domestic issues).
Due to the limitations associated with the use of classical antibiotics, extensive studies have been focused on finding novel, efficient and non-resistance inducing antimicrobial/antibacterial agents.
Within these studies, a novel class of short, naturally occurring peptides, which exert outstanding antimicrobial/antibacterial activity, was uncovered. These peptides, which are known as antimicrobial peptides (AMPs), are derived from animal sources and constitute a large and diverse family of peptides, which may serve as effective antimicrobial agents against antibiotic-resistant microorganisms, as discussed in some recent reviews [7-12].
AMPs are now recognized to have an important role in the innate host defense. They display a large heterogeneity in primary and secondary structures but share common features such as amphiphatic character and net positive charge. These features appear to form the basis for their cytolytic function.
On top of the ribosomally synthesized antimicrobial peptides that have been identified and studied during the last 20 years, thousands of de-novo designed AMPs, were developed [13]. These de-novo designed peptides are comprised of artificially designed sequences and were produced by genetic engineering or by chemical peptide syntheses.
AMPs are attractive targets for bio-mimicry and peptidomimetic development, as reproduction of critical peptide biophysical characteristics in an unnatural, sequence-specific oligomer should presumably be sufficient to endow antibacterial efficacy, while circumventing the limitations associated with peptide pharmaceuticals [14].
One of the challenges in designing new antimicrobial peptides relies on developing peptidomimetics that would have high specificity toward bacterial or fungal cells, and consequently, would allow better understanding of the mechanism underlying the peptide lytic specificity, i.e., discrimination between cell membranes. Structure-activity relationships (SAR) studies on AMPs typically involve the systematic modification of naturally occurring molecules or the de-novo design of model peptidomimetics predicted to form amphiphatic alpha-helices or beta-sheets, and the determination of structure and activity via various approaches [13], as follows:
Antimicrobial peptides can act in synergy with classical antibiotics, probably by enabling access of antibiotics into the bacterial cell [15, 16]. Other potential uses include food preservation [17-20], imaging probes for detection of bacterial or fungal infection loci [21-23] and lining of medical/surgical devices [24].
However, while the potential of AMPs as new therapeutic agents is well recognized, the use of the presently known AMPs is limited by lack of adequate specificity, and optional systemic toxicity [25-27]. Thus, there is a clear need for developing new antimicrobial peptides with improved specificity and toxicity profile.
Moreover, although peptides are recognized as promising therapeutic and antimicrobial agents, their use is severely limited by their in vivo and ex vivo instability and by poor pharmacokinetics. Peptides and polypeptides are easily degraded in oxidative and acidic environments and therefore typically require intravenous administration (so as to avoid, e.g., degradation in the gastrointestinal tract). Peptides are further broken down in the blood system by proteolytic enzymes and are rapidly cleared from the circulation. Moreover, peptides are typically characterized by poor absorption after oral ingestion, in particular due to their relatively high molecular mass and/or the lack of specific transport systems. Furthermore, peptides are characterized by high solubility and therefore fail to cross biological barriers such as cell membranes and the blood brain barrier, but exhibit rapid excretion through the liver and kidneys. The therapeutic effect of peptides is further limited by the high flexibility thereof, which counteracts their receptor-affinity due to the steep entropy decrease upon binding and a considerable thermodynamic energy cost. In addition, peptides are heat and humidity sensitive and therefore their maintenance requires costly care, complex and inconvenient modes of administration, and high-cost of production and maintenance. The above disadvantages impede the use of peptides and polypeptides as efficient drugs and stimulate the quest for an alternative, which oftentimes involves peptidomimetic compounds.
Peptidomimetic compounds are modified polypeptides which are designed to have a superior stability, both in vivo and ex vivo, and yet at least the same receptor affinity, as compared with their parent peptides. In order to design efficacious peptidomimetics, an utmost detailed three-dimensional understanding of the interaction with the intended target is therefore required.
In conclusion, most of the presently known antimicrobial peptides and peptidomimetics are of limited utility as therapeutic agents despite their promising antimicrobial activity. The need for compounds which have AMP characteristics, and are devoid of the limitations associated with AMPs is still present, and the concept of providing chemically and metabolically-stable active compounds in order to achieve enhanced specificity and hence enhanced clinical selectivity has been widely recognized.
U.S. patent application Ser. Nos. 11/234,183 and 11/500,461 and WO 2006/035431, by the present assignee, which are incorporated by reference as if fully set forth herein, teach a novel class of antimicrobial polymers which were designed so as to circumvent the limitations associated with antimicrobial peptides, and which are composed of hydrophobic moieties and amino acids. The teachings of these patent applications show that in order to achieve an active antimicrobial agent devoid of the drawbacks of classical antibiotic agents, and those of AMPs, three key attributes of AMPs need to be maintained: a flexible structure, an amphiphatic character and a net positive charge. As successfully presented in these patent applications, these novel active antimicrobial polymers are achieved by the use of positively charged amino acids and the use of non-amino acid hydrophobic moieties, such as, fatty acids and the likes, which will not only achieve the desired amphiphatic trait and resolve the production and maintenance issues limiting the use of polypeptides as drugs, but also alleviate the sever limitations restricting the administration of polypeptides as drugs.
As further demonstrated in U.S. patent application Ser. Nos. 11/234,183 and 11/500,461 and WO 2006/035431, this newly developed class of polymers has been shown to exhibit high antimicrobial activity, low resistance induction, non-hemolyticity, resistibility to plasma proteases and high affinity to microbial membranes.
While the antimicrobial polymers taught in U.S. patent application Ser. Nos. 11/234,183 and 11/500,461 and WO 2006/035431 indeed exhibit the desired properties and were shown to overcome the limitations associated with common antimicrobial agents as well as AMPs, other polymers which are based on the characteristics discussed hereinabove, having yet different structural attributes can be designed and used advantageously as antimicrobial agents.
There is thus a widely recognized need for, and it would be highly advantageous to have, metabolically-stable, non-toxic and cost-effective antimicrobial agents devoid of the above limitations.
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