Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 8, Issue 4, 2009

Every year the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meets in the Fall, to chronicle and describe the state-of-the-art in infectious diseases and chemotherapy, with the hope of highlighting new agents that look promising to treat Mankind's most dreaded pathogens. Unfortunately, this year fewer new agents are being described, although the clinicians will be out in full force, looking for agents and methods with which to treat their patients. Fortunately, the motivations and efforts of drug-discovery researchers and medicinal chemists are still in full force too, looking for novel agents and chemicals with which to treat bacterial and otherwise diseases, some of which are chronicled here, in the current Hot Topic: Newer Agents Against Biofilms, Fungi, Bacteria and Parasites. Our Guest Editor, Dr. Paul Savage of Brigham Young University, comments on the first two papers in the segment on Biofilms, and describes in detail with his colleagues their own research using the ceragenins and their derivatives against biofilm formation, in Activities of Ceragenin CSA-13 Against Biofilms in an In Vitro Model of Catheter Decolonization. This review by Dr. Savage and his colleagues shows that scaffolds other than typically encountered in chemotherapy can be used to affect biofilm formation in medical devices, a common source of potential infection. Small molecule approaches toward the non-microbicidal modulation of bacterial biofilm growth and maintenance-Justin J. Richards and Christian Melander- North Carolina State University.

Bacterial biofilms on medical devices are a primary source of infection, and efforts have been made to develop means of decontaminating colonized devices including hemodialysis catheter “lock” solutions. Because bacterial biofilms are inherently resistant to many antibiotics and widespread use of antibiotics contributes to resistance development, there is a need for new approaches to biofilm eradication. We have developed a class of compounds, termed ceragenins, that mimic the antimicrobial activities of antimicrobial peptides. The ceragenins are active against established biofilms. We tested solutions of a lead ceragenin, CSA-13, with and without EGTA against biofilms comprised of Gram-negative and positive organisms. Similar solutions containing ciprofloxacin were used as comparators. The ceragenin solutions eradicated biofilms at concentrations comparable to those required for eradication by ciprofloxacin. However, against a methicillin- resistant strain of Staphylococcus aureus, CSA-13 proved to be far superior to ciprofloxacin.

Bacterial biofilms are defined as a surface attached community of microorganisms that are protected by an extracellular matrix of biomolecules. Within a biofilm state, bacteria are more resistant to antibiotics and are inherently insensitive to antiseptics and basic host immune responses. The NIH has estimated that 65-80% of all microbial infections are biofilm-based. Biofilm infections of indwelling medical devices are also of major concern, as once the device is colonized, infection is virtually impossible to eradicate. Bacterial biofilms underlie the persistent colonization of hospital facilities, which perpetuates nosocomial infections. Hospital-acquired infections place a $10 billion burden on the U.S. healthcare system annually. Given the prominence of biofilms in infectious diseases, there has been an increasing effort toward the development of small molecules that will modulate bacterial biofilm development and maintenance. This, coupled with the spread of multi-drug antibiotic resistance across many of these bacteria, has put a tremendous burden on the scientific and medical community to alleviate biofilm-related problems. In this review, we will highlight the development of small molecules that inhibit and/or disperse bacterial biofilms through non-microbicidal mechanisms. The review will be segmented into providing a general overview of how bacteria develop into biofilm communities, why they are important, and the difficulties associated with their control. This will be followed by a discussion of the numerous approaches that have been applied to the discovery of lead small molecules that mediate biofilm development. These approaches are grouped into: 1) discovery/synthesis of molecules based upon naturally occurring bacterial signaling molecules, 2) chemical library screening, and 3) discovery/synthesis of natural product and natural product analogues.

Bacteria rely on chemical communication or quorum sensing to coordinate activities necessary for their survival in colonies. Among the numerous processes mediated by this intercellular communication is the formation of biofilms. The prevalence of biofilms in many different environments can be problematic. Their association to infectious diseases and their inherent ability increase antibiotic resistance in bacteria has led to a groundswell of research focused on new methods to control them. Their dependence on quorum sensing has made those signaling systems within bacteria an attractive target for the design of new therapeutic agents. Compounds that can disrupt this process are termed quorumsensing inhibitors (QSIs). By disrupting the biofilms, thereby making the bacteria more susceptible to traditional antibiotics, these QSIs may provide the newest weapon in the therapeutic arsenal against infections involving drug-resistant bacteria. These QSIs can come from a variety of sources and have a wide array of structures. This review will cover the scope of QSIs that have been reported in the literature, in particular those that have been shown, or may have potential, to inhibit biofilm formation and development.

The antimicrobial peptides represent diverse structures for drug design. They have been looked at as potential sources of new antimicrobial drugs to combat the increasing threat posed by multiple drug resistant microorganisms. Unfortunately, peptides themselves provide inferior drug candidates because of their low oral bioavailability, potential immunogenicity, poor in vivo metabolic stability, high molecular weight and most importantly being exposed by enzymes like proteases. Recent efforts to resolve disadvantageous peptide characteristics, and thus generating practical pharmaceutical therapies, have focused on the creation of non-natural peptide mimetics. Peptidomimetic molecules may have reduced immunogenicity and improved bioavailability relative to peptide analogues. Also the artificial backbone makes most peptidomimetics resistant to degradative enzymes thus increasing the stability of peptidomimetic drugs in the body. In this article, after introducing antifungal peptides, benefits and limitations, and peptidomemetics usage are discussed and applications in drug discovery process and antifungal research will be presented.

The therapy of parasitic diseases has relied, until recently, on the use of a very limited number of drugs, most of them of low efficacy, leading to side effects and in certain cases with high toxicity. This review focuses on the chemotherapy to treat diseases caused by Trypanosoma cruzi (Chagas' disease), Trypanosoma b. gambiense and Trypanosoma b. rhodesiense (sleeping sickness), Plasmodium (malaria) and Leishmania (leishmaniasis). Therefore, we will summarize drugs currently available and future specific chemotherapy against these neglected diseases under clinical evaluation. The most advanced antichagasic candidates are represented by posaconazole, TAK-187 and albaconazole, which have completed their pre-clinical development as anti-T. cruzi agents, while new quinines concerning to ferroquine, tafenoquine and AQ-13 are in phase I or II of clinical trials as promising candidates for the treatment of malaria. Although parafuramidine has been under phase III clinical trials to treat Human African Trypanosomiasis (HAT), its development was discontinued due to liver problems. Finally, new approaches for the treatment of leishmaniasis were achieved by using miltefosine and, more recently, the aminoglycoside paromomycin, which was approved after clinical trials and, owing to its milder adverse effects and low cost, is being considered as a potential first-choice treatment for the disease. Thus, this review aims to highlight the available drugs to treat four endemic parasitic diseases, as well as promising therapeutic approaches and their corresponding targets under development, but it is not intended to be an exhaustive survey on the subject.

Polymyxin B (PMB) belongs to a class of antibiotics discovered more than six decades ago. PMB was used for various bacterial infection threatening, in particular to sepsis. Its use, however, was abandoned because of the observation of severe side effects. In the last years this view changed due to the appearance of multi-drug resistant Gram-negative pathogens, which were resistant to most available antibiotics, leading to a re-evaluation of the polymyxin antibiotics (PMB and PME). Although there is a large market potential for the development of drugs to fight sepsis, the available successful clinical strategies are very limited. The cause for this lies in the clinical failures of a number of drug candidates, which were tested in the last years. This was attributed to some extent to our elementary understanding of the pathophysiology of sepsis, to not optimally designed clinical trials and a lack of appropriate pre-clinical models to establish the proof of concept (POC). At that time there were just humble knowledge about the structural mechanisms involved in the advantageous aspects of PMB-endotoxin interactions to increase the knowledges outcome in sepsis therapy. Therefore, the current paper describes the clinical aspects of PMB application in bacteraemia and sepsis therapy. However, the focus of the presented paper lies in the structural and mechanistic aspects of PMB-endotoxin (LPS: lipopolysaccharide) recognition and how this knowledge can be applied for the development or improvement of new clinical drug candidates to support sepsis therapies. Due to chemical similarities between PME and PMB, certain aspects of the use of PME as an antimicrobial agent and in sepsis therapy are considered and compared to PMB.