Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 8, Issue 1, 2009

Antibiotic discovery and development have undergone major changes in the new millennium, namely changes in the molecular chemotypes that are being examined as new anti-infectives and in regimens of treatment. Chemical structures that were of minor scientific interest years ago, now have more research devoted to them by diligent and determined researchers throughout the world- and this is happening for a number reasons. The first and foremost is that it is getting more and more difficult to keep up with antibiotic resistance mechanisms, as the generations of penicillins, cephalosporins and other common antibiotics increase in number and decrease in activity. The second major reason for renewed interest in other families of molecules is that it is just getting more difficult to chemically modify and deliver active antibiotics, as mechanisms of resistance increase. The goal of this review journal, as I see it as the Editor-in-Chief, is to follow the scientific trends in antibiotic drug discovery, development and chemotherapy, and report back to the reader, illuminating the complexities and findings of the different families of antibiotics, particularly in regards to their structure-versus-activity profiles, in an approving nod to all medicinal chemists. It is also hoped that from this journal and the information it presents other advances in antibiotic evolution occur, from the motivation and insight gained from our authors in the various contemporary and timely topics. And as antibiotics evolve, so will our ability to treat infectious diseases-eventually. The editorial and advisory board members (EABM) of Anti-infective Agents in Medicinal Chemistry are researchers and experts active in diverse fields of chemotherapy devoted to infectious diseases, and with Bentham Publishers, make every effort to deliver the most current and relevant topics and scientific fronts in their fields. The time they spend composing, writing and editing is considerable and admirable, seeking to increase and compile the body of knowledge for future researchers, and to help their field progress and evolve. After all, in a changing biological world you either adapt or die, and this rudimentary adage is applicable to anti-infective agents and the future of chemotherapy. This special issue highlights the research interests of members of our Editorial and Advisory Board, experts in different fields that strive to educate others of the importance of their studies and detail the molecular worlds they can share. Our article on Polyfunctional Antibiotics Affecting Bacterial Cell Membranes, written by myself and my colleagues at Paratek and microbiologist Dr. Susan Barbaro of Rivier College, presents a series of families of compounds of increasing molecular complexity that have one common mechanistic feature- the ability to perturb bacterial membranes and affect antibiosis. This common denominator is also the reason behind the recent success of Cubist Pharmaceuticals and their lipopeptide Cubicin® for use against resistant bacteria and in complicated skin and tissue infections. From the study of these other families will no doubt evolve newer and more potent antibiotics with increased specificity for bacteria and less toxic side effects in mammals. The families presented range from low molecular weight compounds to the broad array of antimicrobial peptides, which by themselves are a separate scientific front and will be the subject of future articles. Continuing in this theme of membrane active agents is the review by Dr. Brandenburg and his colleagues, describing their studies of the antimicrobial and anti-inflammatory peptide melittin and its effects on cellular membranes. Here, their group describes the mechanisms of action of melittin in great detail using the latest methods in analytical chemistry to understand and correlate with biological test systems. Their efforts demonstrate the state-of-the-art in membrane physiology and binding stoichiometry and are novel methods for studying bacterial and mammalian cell membranes while they further the evolution of science. One area of antibiotic evolution that is a divergence from the normal is the finding that certain classes of antibiotics have other mechanisms of action as anti-inflammatory agents in eukaryotic cells and may show therapeutic benefit in mammals. Drs. Konaklieva and Plotkin and their colleague T. Herbert explain their findings and activities of the β-lactam family of antibiotics against eukaryotic cells, particularly those involved in neural tissue. The β-lactams hold promise as neuroprotectants independent of their antibiotic effects, and out of the large number of compounds synthesized in the past they surely will emerge as SAR and clinical candidates.

The β-lactam family of antibiotics, the penicillins and cephalosporins, act primarily at the level of the bacterial membrane by inhibiting membrane proteins associated with cell wall synthesis. As a family they represent some of the most clinically relevant antibiotics known, although antibiotic resistance has limited the use of older generation β-lactams, novel compounds are currently emerging from research efforts worldwide. Fortuitously, there are other families of antibiotics of peptide-derived origin and possessing polyfunctional chemical groups-compounds with complex and multiple pharmacophores with biological function- that also act at the level of the bacterial membrane. Polyfunctional antibiotics interfere with bacterial growth by direct interaction with the cell membrane lipid bilayer and its constitutive array of metabolically active enzymes and structural proteins.

Up to now the details of the mechanisms of melittin action on biological bilayer model systems in dependence on lipid composition, in particular on the kind of head groups, temperature, and ionic strength are not well understood. In particular, the influence of cholesterol present in most eucaryotic cells and the influence of glycolipids present in bacterial membranes are far from being clear. Here, data are presented from investigations by small-angle X-ray scattering (SAXS), Fouriertransform infrared spectroscopy (FTIR), circular dichroism (CD) spectroscopy, Forster resonance electron transfer (FRET) spectroscopy, and calorimetric techniques (DSC: differential scanning calorimetry and ITC: isothermal titration calorimetry) on the interaction of melittin with different (glyco)lipids, in order to elucidate 1) the peptide secondary structure during the melittin-lipid interaction, 2) to monitor the intercalation of the peptide into membranes, 3) to characterize the aggregate structure of the lipids, 4) to characterize the influence of lipid:melittin ratio with regard to the acyl chain melting behaviour as well as 5) to determine the peptide-lipid binding stoichiometry. These experiments are correlated with results from biological test systems, in which the inhibition of the lipopolysaccharide-induced cytokine expression in human immune cells by melittin was monitored. Furthermore, the findings are related to data found in literature with various membrane systems and different techniques. In this way, it is now possible to better understand the details of the melittin-membrane interactions, which is important with respect to the understanding of its anti-inflammatory and antimicrobial properties.

Although, β-lactams have historically been viewed as a class of antimicrobials, in the last few decades their role as inhibitors of bacterial enzymes has been expanded. Their inhibitory activity is based on their ability to acylate enzymes, majority of which have serine as nucleophile in the active site. In addition to being inhibitors of bacterial enzymes, β-lactams also inhibit viral and mammalian serine enzymes. Recently, a blinded screening of 1,040 FDA approved drugs and nutritional compounds, has demonstrated an additional utility both in vitro and in vivo of β-lactam antibiotics (penicillins and cephalosporins) as protectors against neuroexcitotoxicity. This neuroprotection is associated with increases in the glial-associated reuptake protein, GLT1, suggesting that β-lactam's neuroprotective effects may be mediated by an increase in glutamate removal from the synapse. The focus of this review is on the evaluation of the potential of β-lactam antibiotics as neuroprotective agents.

Recent years have witnessed emergence of resistance to azoles and other antifungal compounds. Moreover, the existing antifungal compounds for the contemporary clinicians are limited in numbers as opposed to available antibacterial compounds. Hence there is a real need to search for newer compounds with potential antifungal activity. In this review, the potential of medicinal plant species to yield newer antifungal agents would be illustrated with an emphasis on compounds discovered in recent years. Some of the issues pertinent to this area, including their botanical, medicinal, and available spectroscopic data, will briefly be reviewed and it is hoped that this would definitely stimulate for their discussions and researches on this important aspect including the mechanism of actions of these recently discovered compounds.

Despite several infectious diseases which have been eradicated or controlled worldwide nowadays, there are still some infectious diseases such as AIDS, caused by HIV, which are supposed to be a serious social health problem and demand the search for new vaccines. A classical approach for generation of vaccines against infection was initially based on the use of killed or attenuated pathogens. With the increase of information about mechanisms governing immune responses after microorganism infection, new approaches have been investigated. The use of dendritic cells (DCs) pulsed with whole pathogen organisms has been considered and explored; however, this approach still presents serious concerns about safety issues. This fact has conducted to a “non-classical” approach where well defined antigens with complete control of molecular design are used. Two strategies are generally envisaged. One is based on the direct stimulation of T and B-cells using immunogenic peptides for producing antibodies and the other one is based on the use of antigen-pulsed dendritic cells producing both cellular and humoral response. This review will be focused on the state of the art of these new approaches for vaccine development to infectious diseases. Synthetic strategies, technical problems, and applications of multivalent dendritic systems will be described and commented. This is a topic of enormous interest which could open interesting alternatives and expectancy in infectious diseases for the development of effective therapies.

Serious attempts to address antibiotic resistance, a worldwide public health concern, have recently become more intensive. In hospital settings, resistance to antibacterial agents has been recognized by clinicians for several decades. Resistant strains are now isolated on a daily basis from patients with community-acquired infections further elevating the level of concern among public health officials. The pharmaceutical industry has generally focused its attentions on chronic therapeutic indications in recent years (e.g. cardiovascular and metabolic diseases), but will likely be forced to reengage in antibacterial discovery efforts as therapeutic options diminish for the treatment of infections caused by multidrug resistant pathogens. The ability to squeeze additional utility out of known classes of antibacterial agents has become limited and antibacterial discovery scientists will need to focus on new approaches and targets. These new approaches will need to include strategies that explicitly address resistance up front and simultaneously attempt to facilitate the slower development of resistance as new compound classes enter clinical use. One approach that can be a useful component of antibacterial discovery efforts and prospectively address resistance is structure-guided design (SGD). This review will describe several recent examples in which SGD was applied as part of a multidisciplinary effort to address antibacterial resistance. These include dihydrofolate reductase inhibitors, broad-spectrum β-lactamase inhibitors, novel oxazolidinones, aminoglycoside mimetics, peptide deformylase inhibitors, and inhibitors that simultaneously target DNA gyrase and topoisomerase IV.