In this review we have tried to present a complete and integrated picture of the old and new ways to discover antibacterial agents. The development of new antibacterial agents can be made from derivatives of known antibacterial agents or by identification of novel agents active against previously unexploited targets. The genetic and biochemical basis of resistance to most classes of antibacterial agents is now known and this has been important in the design of a rational strategy that can be used to counteract resistance. This strategy can follow two approaches: i. Modification of the basic structure of the antibacterial agent, which circumvents antibacterial resistant mechanisms, and ii. Development of a compound inhibiting the mechanism of resistance for an antibacterial agent, hence the concomitant administration of the antibacterial agent plus the inhibitor, as a co-drug, will potentiate this activity. There are also two main approaches to find new protein targets: 1. Classical and, 2. Genomic. The first includes the study of secondary metabolites of bacteria and fungi with antibacterial activity, and it has now been expanded to include plant extracts and marine macro- and microorganisms, as well as non-cultivable soil bacteria. Recent tools such as comparative genomic, combinatorial chemistry, and computerized modelling have helped in the development of new antibacterial agents. Finally, other approaches, such as bacteriophages, antisense RNA and proteins involved in pathogenicity to find new antibacterial drugs are currently investigated. Keywords: new antibacterial agents, antibacterial resistance, comparative genomic, comparative chemistry
Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide. Although a treatment of limited efficacy exists, there is an urgent need for potent antivirals that can specifically target the viral proteins that are essential for replication. We recently reported the discovery of BILN 2061, a selective and potent inhibitor of the HCV NS3 protease. When administered to HCV infected patients for two days, BILN 2061 produced an unprecedented and rapid decrease in viral load, thus demonstrating the first proof-of-concept for a new class of HCV antiviral. The BILN 2061 family of compounds was rationally designed from a peptidic substrate using dynamicsand structure-based strategies. In this review, we present an overview of the novel strategies that led to the BILN 2061 family of compounds. It includes the discovery of the original peptide as a lead, the identification of important substituents that directly contact the protease pocket, the determination of the free and protease-bound structure and dynamics features of the compounds, and the rational use of such data for medicinal chemistry purposes. Central to this was an ongoing effort to qualitatively elucidate the binding modes/roles of each substituent using a combination of data from NMR spectroscopy, structure-activity relationships, and X-ray crystallography. In addition to achieving the desired goal of initiating clinical trials with a potent inhibitor with good pharmacokinetic properties, the methodologies developed for targeting this unusual and difficult protease, which has a shallow and relatively featureless binding pocket, are expected to have general utility in other medicinal chemistry efforts. Keywords: chronic hepatitis c, cirrhosis, hcv genotypes, replication assay, human hepatoma cell line, protease domain, nmr
Infection with HCV is a global concern. Estimates from the WHO suggest that over 170 million people are infected worldwide with over 2.7 million people infected in the US. Current therapies including interferon (IFN-α) and ribavirin are ineffective against many HCV genotypes and a sustained viral response is difficult to achieve in many HCV patients. Inconvenient dosing regimens and overall toxicity conspire to make these current therapies inadequate. Although the recent development of pegylated interferons have shown signs of improved genotype applicability and reduced toxicity, it is believed that alternative therapies will be needed to battle this disease on a global scale. The incidence of HIV/HCV co-infection is a growing trend and our ability to effectively treat these patients is anticipated to be a significant medical challenge. For HIV-1, the successful development of nucleotide- and non-nucleotide-based reverse transcriptase inhibitors (NNRTIs) as well as HIV protease inhibitors (PIs) has afforded patients a variety of treatment options. Although 5-times more prevalent than HIV-1 infection, the development of target-directed HCV treatments has been less successful. Like HIV, the two HCV targets receiving the most attention are the protease (NS3-4A) and the polymerase (NS5B). Recently, the discovery of several classes of allosteric HCV NS5B inhibitors have been reported in the patent and scientific literature and many have made their way into clinical trials. This review will describe the nature of these novel inhibitors while drawing comparisons and contrasts to the structural biology, development, and clinical utility of HIV NNRTIs. Keywords: viral hepatitis c (hcv), hemolytic anemia, rna viruses, polymerases, site-directed inhibitors
The extensive use of antimicrobials in community as well as nosocomial environments during the last half century has created a pressure that is able to select resistant microorganisms, transforming this “evolution” into one of the most dangerous phenomena of the last twenty years. Two different aspects of the same problem have to be examined: the appearance of “new opportunistic multiresistant microorganisms, and the assembly of resistance related genetic elements from heterologous sources in well known pathogens. In both cases, the bacterial response to this selective pressure is the acquisition and spread of a variety of determinants due to mutations of normal cellular genes, acquisition of foreign resistance determinants or a combination of these two genetic mechanisms. All these processes are generally present in contemporary Gram-positive pathogens that have evolved and spread over the last twenty years becoming a special, and perhaps unique, threat for the emergence of resistance in our era. Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Enterococci, which are currently isolated, are no longer the same organisms isolated 50 years ago: becoming multiresistant or predominant opportunistic pathogens, they have paid a “biological price” to the use of antibiotics in a short time period. Once established, a resistant strain may persist under selective pressure from numerous antimicrobials, furthermore, some resistances are widespread and others local, but it is still unclear why some bacterial lineages achieve epidemic spread whereas others, that are equally resistant, do not. Many interesting new antibiotics have been developed and recently marketed or are undergoing phase III clinical trials. These drugs, some of which have novel mechanisms of action, may help to counterbalance and, if used appropriately, prevent the spread of resistant bacteria. This review will consider some of these new drugs such as streptogramins, oxazolidinones, the newer fluoroquinolones, ketolides, daptomycin, new glycopeptides, glycylcyclines and the newer cephalosporins. Keywords: gram-positive, resistance, multiresistant strains, mutations, genetic units, oxazolidinones, daptomycin, ramoplanin, ketolides, oritavancin
The design and optimisation of the second-generation antibacterial oral streptogramin is reported in terms of semi-synthesis, structure-activity relationships, pharmaco-kinetics properties and antibacterial activities. Our endeavours led to the selection of two new combinations RPR131166/RPR132493 (30/70) and RPR202868/RPR132552 (30/70) whose antibacterial properties will be reported in detail. The overall profile of the latter association, which is currently undergoing clinical development, suggests that it could be useful for the treatment of community-acquired infections. Keywords: antibacterial, streptogramins, pristinamycins, synergy, ribosome, structure-activity relationships, semi-synthesis
Trypanothione reductase is an enzyme that is unique to organisms belonging to the family Trypanosomatidae. Certain trypanosomatids, including trypanosomes and leishmania, are parasitic protozoa that are responsible for several devastating diseases. Trypanothione reductase plays a pivotal role in maintaining the redox balance of trypanosomatids, thus the development of inhibitors of trypanothione reductase may lead to the design of new drugs to combat diseases caused by parasitic trypanosomatids. Trypanothione reductase catalyzes the NADPH-mediated reduction of a glutathionespermidine conjugate named trypanothione. Several classes of trypanothione reductase inhibitors have been developed and discussed in recent reviews. However, less attention has focused on the interactions of inorganic compounds with trypanothione reductase. This is an intriguing area, since many of the current drugs used to treat trypanosomatid infections are metal-based complexes, containing either arsenic or antimony, and several of these compounds interact with trypanothione and/or trypanothione reductase. Thus, although the trypanocidal activities of these drugs involve several mechanisms, one site of action may be trypanothione reductase. In this review, the major diseases caused by Trypanosomatidae, current drugs, drug resistance, and an overview of trypanothione and trypanothione reductase are summarized. Recent work on the development of metal-based inhibitors of trypanothione reductase (including platinum(II) complexes) and interactions between certain inorganic compounds (including antimony(III), antimony(V) and arsenic(III) complexes) and trypanothione are discussed. Finally, studies of a range of natural products that inhibit trypanothione reductase are summarized. Keywords: trypanothione reductase, trypanosome, leishmania, trypanosomatid, arsenic, antimony, platinum, bisbenzylisoquinoline alkaloids
A large number of chemical enteties, immunogens and topical medications, either synthetic or naturally occuring, against HIV have been brought into focus to combat AIDS epidemic. The three major classes of anti-HIV medications, leading to the development of synthetic drugs worldwide, belong to NRTs, NNRTIs and protease inhibitors. These have been discussed in detail with regard to HIV infected patients. A large number of natural products isolated from various plant species, flora and fauna have been described in detail. Some of these compounds have the potential for development as future drugs for cure of AIDS and could be helpful in replacement of combination therapy presently prevalent for treatment of HIV patients. Proteomics and Genomics are vital cores of biotechnology for prime consideration in lead generation aginst HIV. The recent aspects of development of combination therapy as well as the development of vaccines for treatment of AIDS, which are of current interest to clinicians, biologists and medicinal chemists also being discussed. Keywords: nrtis, nnrtis, pIs, combination therapy, natural products, proteomics, genomics, vaccine
By the early nineteen seventies the mechanism of inhibition of peptidoglycan biosynthesis by various cell wallactive antibiotics was well established, and the Gram-positive bacterium Staphylococcus aureus had often been used in the studies. From the early days of penicillin it was known that cell wall-active antibiotics are typically bactericidal causing cell death and lysis, a phenomenon that has recently been described as programmed cell death. Uncovering the details of the molecular and cellular events occurring subsequent to inhibition of peptidoglycan biosynthesis, a legitimate aspect of knowledge of the mode of action of these agents, has had to await the advent of the omics era-genomics, proteomics and transcriptomics-over the past several years. Genome-wide transcriptional profiling using DNA microarrays of the response of S. aureus to challenge by cell wall active antibiotics has revealed a cell wall stress stimulon of genes upregulated in their expression by these agents. Several of the genes encode proteins involved in cell wall metabolism and their induction can be regarded as a response of the organism to preserve and repair the compromised cell wall. Expression of a significant number of cell wall stress stimulon member genes is controlled by a two-component regulatory system. Cell wall stress stimulons regulated by two-component systems have also been described in Bacillus subtilis and Listeria monocytogenes, and are probably common to all Gram-positive bacteria. Unfortunately S. aureus has not remained susceptible to cell wall-active antibiotics and methicillin-resistant strains are common, and vancomycinintermediate and-resistant strains have arisen. Interestingly, some member genes of the cell wall stress stimulon have been previously encountered in the context of methicillin-resistance or vancomycin-intermediate resistance. There is a threat of pan-resistant S. aureus strains and new antimicrobial agents are needed. Cell wall biosynthesis remains a viable target for new drugs, and recognition of the transcriptomic signature of the cell wall stress stimulon can be used to indicate a cell wall mode of action. Individual cell wall stress member genes may form the basis of a screen for cell wall-active agents. Finally, agents targeting cell wall stress stimulon member gene expression or proteins might enhance the activity of cell wall-active agents that induce the cell wall stress stimulon.
Streptococcus pneumoniae is the most important bacterial cause of pneumonia and meningitis among adults. It is also a common cause of bacteraemia among HIV infected adults with rates of disease approaching 100 times normal community incidence figures. Rates of antibiotic resistance are rising among pneumococcal isolates globally and the currently available 23-valent pneumococcal polysaccharide vaccine is ineffective in HIV infected adult populations. The newer conjugate vaccine has been highly effective in children in the developed world. It may also offer some promise in adult risk populations, but it is expensive and has limited serotype coverage. This article reviews the epidemiology of pneumococcal disease, the current state of pneumococcal vaccines, the pathogenesis of pneumococcal disease, the potential advantages of an inhaled vaccine in adults and some of the chemical obstacles to producing such a vaccine. Keywords: streptococcus pneumoniae, pneumococcal disease, vaccination, inhalation, innate immunity
Highly active antiretroviral therapy regimens (usually three-drug combinations) have shown undisputable efficacy in the reduction of the morbidity and mortality of HIV-infected patients. However, these regimens are only virustatic, which means that, in order to suppress viral replication, treatments should be maintained for life, without any additional benefit over time once immune restauration has been obtained. Besides, there is a debate on when to start therapy because profound immunodepression may not be totally reversible, recognizing that earlier treatment means longer drug exposure. On the other hand, the long-term toxicity of these drugs has generated new problems such as the appearance of the lipodystrophy syndrome and the increase of cardiovascular morbidity observed in patients treated for several years, particularly with HIV protease inhibitor-containing regimens. Therefore, new drugs are needed, not only for patients experimenting virological failure but also for successfully treated patients, in order to reduce toxicity, and these new drugs must now be screened for metabolic disturbances and adipocyte toxicity as well as for antiretroviral activity. Alternatively, new strategies, such as specific or non-specific immune-based therapy, reinforcing drug efficacy or allowing treatment interruptions, must be developed. Keywords: highly active antiretroviral therapy, infection, immune restoration, nucleosidic inhibitors, dna polymerase, cardiovascular risk, protease inhibitor
Farnesyltransferase catalyzing the transfer of a farnesyl residue from farnesylpyrophosphate to the thiol of a cysteine side chain of proteins carrying the C-terminal CAAX-tetrapeptide sequence has been one of the prime targets in the development of novel anti-cancer agents. From numerous farnesyltransferase inhibitors that have been described, several have reached advanced stages of clinical trials. In addition to mammals, farnesyltransferases were also identified in different pathogenic protozoa including Plasmodium falciparum, the causative agent of malaria tropica. Therefore, inhibition of farnesyltransferase has also been suggested as a new strategy for the treatment of parasitic infections. The overall sequence identity of human and P. falciparum farnesyltransferase is considerably low, however, amino acid differences in the active sites are rather small. Only few inhibitors have been assayed against P. falciparum farnesyltransferase; some of them displayed high activity against the isolated enzyme but were only moderately active when assayed against blood stages of P. falciparum. A number of established farnesyltransferase inhibitors or derivatives of them are highly active against the human enzyme or against human cancer cells, but generally displayed only micromolar activity against P. falciparum blood stages. However, there are examples of various inhibitors with nanomolar in vitro activity against P. falciparum. In a mouse model, activity has also been demonstrated in vivo. This may justify further efforts in the development of specific anti-malarial farnesyltransferase inhibitors. Keywords: malaria, plasmodium falciparum, farnesyltransferase inhibitors, protein prenylation
Current strategies for the treatment of human immunodeficiency virus (HIV) infection are based on cocktails of drugs that target the viral entry step and the enzymes reverse transcriptase or protease. At present, the clinical benefit of this combination therapy for HIV-infected patients is considerable, although it is not clear how long this effect will last taking into account the emergence of multiple drug-resistant viral strains. Addition of new anti-HIV drugs targeting additional steps of the viral replication cycle may increase the potency of inhibition and prevent significant resistance development. During HIV replication, integration of the viral genome into the cellular chromosome is an essential step catalyzed by the viral integrase. Although HIV integrase is an attractive target for antiviral therapy and the focus of intensive research, to date only two classes of compounds that selectively inhibit HIV integration have been identified, namely the diketo acids and the pyranodipyrimidines. In this review we address the question why it has proven so difficult to find potent and selective integrase inhibitors; we point to potential pitfalls in defining an inhibitor as an authentic integrase inhibitor and we propose new strategies and new technologies for the discovery of genuine HIV integration inhibitors. For the diketo acids and the pyranodipyrimidines we will discuss in detail the antiviral activity, the molecular mechanism of anti-HIV action, the in vitro HIV resistance development and the clinical perspectives. Keywords: integrase, inhibitors, resistance, ledhgf
Eradication of the pathogen has historically served as a key endpoint in clinical trials of anti-infective therapy. Studies of anti-tuberculous therapy have established the general principle that the rate of clearance of M. tuberculosis may serve as a surrogate marker for the adequacy of its eradication. The best studied of these markers is sputum culture conversion after 2 months of chemotherapy. Closely related measures include time to sputum culture conversion, and serial assessment in sputum of CFU counts, mycobacterial antigens and host cytokines. These are now supplemented by an ex vivo infection model in which the capacity of host immune mechanisms and administered chemotherapy to kill intracellular M. tuberculosis is assessed using whole blood culture. The validation of new surrogate markers that reliably predict relapse of tuberculosis is essential if the pace of clinical research in tuberculosis is to be accelerated. Keywords: anti-infectious agents, pyrazinamide, chemotherapy, sputum b (alpha) antigen, sputum cytokines, radiography, time to positivity
This review addresses key medicinal chemistry issues relevant in the discovery and development of CCR5 and CXCR4 antagonists as anti-HIV drugs. Recent progress in the discovery and development of such antagonists, SAR and clinical status are reviewed.
At least as long ago as the ancient Egyptians, sulfur-bearing natural products have been used for their potent medicinal properties. Although extracts from leeks were the earliest sulfur-containing substances to be employed for treatment of microbial and parasitic infections, a wide variety of natural and synthetically derived organosulfur compounds have been found to possess important antibiotic properties. There now exist, for virtually every class of human infection, representative examples of organosulfur anti-infective agents. By definition, these anti-infectives are compounds capable of preventing, inhibiting, or treating one or more types of infection. Except for their sometimes pungent odor and chemical instability, most antimicrobially active organosulfur compounds display few ill side effects. Given this era of drug resistance in which there is an ever-increasing demand for new antibiotics, organosulfur compounds may provide leads to novel therapies. In this review, we survey the microbiological properties and biochemical behavior of those organosulfur compounds whose activity depends specifically on the reaction of the organosulfur functionality with a biological target. The most common or likely mechanistic pathways by which these interactions occur are presented as a means to better understand the compounds modes of action, and to appreciate the opportunities that may exist towards designing yet even more effective anti-infective agents.
CycloSal-BVDUMP triesters 32-34 5-[(E)-2-bromovinyl]-2-deoxyuridine (BVDU 2) have been studied with regard to their potential anti-EBV activity. In addition to the 3-unmodified cycloSal-BVDUMP triesters 32a-f, the 3- hydroxyl function has been esterified with different aliphatic carboxylic acids (33a-g) and α-amino acids having natural and non-natural Cα-configuration (34a-m). In addition to the synthesis of these compounds, different physicochemical properties will be reported, i.e. lipophilicity and hydrolysis behaviour. It could be shown that BVDUMP and not 3,5- cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 32c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3-ester derivatives were devoid of any antiviral activity, while the 3-aminoacyl derivatives showed an antiviral activity, in dependence of the amino acid and the Cα- configuration. In addition, all cycloSal-BVDU phosphotriesters proved to be potent and selective inhibitors of herpes simplex virus type 1 replication. Several pronucleotide concepts will be briefly summarised but the cycloSal-pronucleotide system described in more detail is the only approach that showed an improvement in antiviral activity of the nucleoside analogue BVDU. Keywords: pronucleotides, cyclosal-prodrugs, ebv, hsv, anti-herpes virus drugs
RSV is the main viral respiratory cause of hospitalization in infants and young children in the United States and in the world. This manuscript discusses the different established and experimental approaches to prevention and treatment of respiratory syncytial virus disease. Therapeutic and preventive strategies are examined considering the mechanisms of viral pathogenesis and protection. Keywords: respiratory tract infections, immunity, ribavirin, bronchodilators
Among the antiviral agents developed for the treatment of human viral infections, nucleoside analogs represent the largest group. However, much remains to do to improve their pharmacokinetic properties, to increase their efficacy, to reduce the selection of drug-resistent strains and to reduce their toxic side effects. Towards this end many nucleotide dimers have been synthesized in the last years in several laboratories. Such compounds have several advantages compared to the administration of nucleoside analogs as single drugs: 1) can act as prodrugs for a slow delivery of monomers in circulation; 2) can be encapsulated into autologous erythrocytes to perform as bioreactors converting a non diffusible dimer into a diffusible nucleoside analog to be released in circulation; 3) can be targeted to macrophages by proper drug targeting systems; 4) can overcome the limiting phosphorylating activities of several infectable cell types; 5) can have the advantage of a combination therapy with the administration of a single compound. In this review, dimers developed in our laboratory will be reported. In particular, the heterodinucleotide AZTpPMPA and the homodinucleotide Bis-PMEA are shown to be able to act as prodrugs when administered to mice releasing the single monomer in circulation. The homodinucleotide AZTp2AZT and the dimer AZTp2EMB once encapsulated in human erythrocytes are converted by erythrocyte enzymes into diffusible nucleosides and slowly released from the carrier cells. The dimers AZTp2AZT, AZTp2ACV, ACVpPMPA, AZTpPMPA and Bis-PMEA were targeted to macrophages where a very effective protection against virus replications was obtained. Thus, nucleotide dimers could be used as effective prodrugs for drug delivery in the treatment of viral infections improving the pharmacokinetic of single moieties and can be efficiently targeted to selected cell types with intracellular release of a phosphorylated (active) nucleoside. Keywords: homodinucleotide, heterodinucleotide, anti hiv-1 activity, anti hsv-1 activity, pharmacokinetic properties, erythrocytes, human macrophages, murine aids
