Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 5, Issue 3, 2006

As the problem of antibiotic resistance to the major families of compounds continues, so grows the efforts and complexity of chemically modifying natural product antibiotics to combat and thwart infectious disease pathogens, the topic of this issue of Current Medicinal Chemistry, Anti-Infective Agents. As chemical modification space disappears around simpler, more synthetically amenable families, such as the β-lactams and the quinolones, researchers around the world have developed synthetic and biological tools to study and synthesize more potent compounds with antibiotics of increasing chemical complexity and synthetic challenge. The goals of such endeavors are straightforward- to derive more potent antibiotics while deriving structure-activity relationships, particularly against antibiotic resistant organisms, while describing their mechanisms of biological action. The contributors to this issue represent current scientific fronts in this area, the chemical modifications of complex antibiotics and insights into their biochemical mechanisms, in families of antibiotics that are progressing to their full therapeutic potential. The first scientific front of considerable interest, based upon the peptide antibiotic superfamily and the approval of daptomycin (Cubicin®) for clinical use against Gram-positive pathogens, is provided by Professor M. Marahiel and colleagues from Philipps-Universität, Marburg, detailing the latest efforts in the chemoenzymatic modification of non-ribosomally synthesized proteins. Such proteins have important commercial, therapeutic and biochemical uses, and the study of the biosynthetic pathways and further chemical modifications holds future promise in the areas of industrial synthesis as well as to produce the next generations of antibiotic agents. Lantibiotics, also active natural product peptides that are post-translationally modified, are a second scientific front that is studied worldwide and the subject of one of the leading research laboratories studying their chemistry and mechanisms of action, led by Professor Robert Kaptein at Utrecht University. The lantibiotics have structure-activity relationships directed to the Lipid-II complex, and both their chemical dynamics, studied by high-field NMR, and biochemical mechanisms are detailed here. Such detailed mechanisms may also serve for the future design and therapeutic implementation of this important family of related antibiotics. The aminoglycosides are an extremely important family of related antibiotics, and are composed of both simple derivatives and more complex compounds, capable of inhibiting the growth of a broad spectrum of bacteria. More importantly, specific aminoglycosides have potent activity against the Gram-negative bacteria, and are used therapeutically for their treatment. However, there are few new derivatives or novel structures that have made it to the clinic, although the scientific front concerning new chemistries applied is considerable. Professor Chang and his colleagues from Utah State University are on the fore-front of such research, and show in detail the efforts worldwide to synthesize or semisynthesize new aminoglycoside derivatives. Carbohydrate chemistry is an extremely complex subject yet will be rewarding, provided that newer derivatives can be used against problematic pathogens, primarily residing with the Gram-negative subset of bacteria. In the future, antibiotics will be more complex, as bacteria become more defensive. The articles herein will hopefully act as the first line in developing more potent and useful compounds, as both compounds and bacteria evolve.

Nonribosomally synthesized peptides constitute a large class of highly diverse natural products, which play an important role in modern medicine. The biological activity of these complex compounds ranges from antibiotics to immunosuppressives, cytostatics to cytotoxics, a fact that makes them attractive scaffolds for drug leads. In more recent years, chemoenzymatic strategies were developed allowing the synthesis and derivatization of several highly important peptide antibiotics, such as the vancomycin-type glycopeptide antibiotics, the family of acidic lipopeptides, as well as streptogramin B compounds. This review gives an overview of both the principles of nonribosomal peptide synthesis as well as its associated tailoring enzymes and the compounds these methods produce.

In the light of emerging bacterial-resistance, novel antimicrobial agents are needed to combat infectious diseases. A group of post-translationally modified peptides called lantibiotics frequently appear from screening of active natural compounds. Many lantibiotics target Lipid II, the essential precursor of bacterial cell wall synthesis. A recently characterised Lipid II-binding motif, the pyrophosphate cage, demonstrates a unique way of targeting bacteria and its conservation amongst many lantibiotics makes it a promising template for novel antibiotics. Evidence suggest the existence of additional Lipid II binding motifs of lantibiotics, the identification of which will rely on a better structural understanding of these unique peptides and their mode of actions. Here we will review the current progress of structural studies on lantibiotics and, more specifically, the Lipid II binding motifs. This may aid the development of lantibiotic structure-based drug design.

Aminoglycosides represent an important resource against infectious diseases. However, the prevalence of aminoglycoside resistant bacteria has limited their clinical efficacy and prompted the renewed interest in the study of resistant mechanisms as well as the development of novel aminoglycoside antibiotics. This review will focus on the latest development in the design and synthesis of novel aminoglycoside derivatives.

Nucleoside reverse-transcriptase inhibitors (NRTIs), including stavudine (d4T), zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC) and abacavir (ABC), inhibit/terminate the reverse transcription of the HIV virus, and markedly improve life expectancy and quality of life in HIV-infected patients. This progress, however, has come at the price of frequent side effects. NRTIs can cause myopathy, cardiomyopathy, pancreatitis, peripheral neuropathy, lipodystrophy, hepatic steatosis, lactic acidosis and/or liver failure. Most of these adverse effects have been ascribed to the inhibition/termination of mitochondrial DNA (mtDNA) replication, thus depleting mtDNA. Among NRTIs, the so-called "D-drugs" (ddC, ddI, d4T) seem to be the most potent inhibitors of mitochondrial DNA polymerase γ and mtDNA replication. mtDNA depletion impairs the synthesis of mtDNA-encoded respiratory chain polypeptides. In turn, the depressed respiratory chain activity can secondarily inhibit fatty acid oxidation (FAO), pyruvate dehydrogenase and the tricarboxylic acid cycle, thus possibly leading to steatosis and lactic acidosis. The partial block in the flow of electrons also increases the generation of reactive oxygen species (ROS) by overly reduced respiratory chain complexes, and can also lead to cell death. Importantly, both the therapeutic effects of nucleoside analogues and their mtDNA-depleting action require their initial transformation into the triphosphate derivatives. This activation pathway competes with conjugation and/or degradation pathways. Exogenous and endogenous factors can diversely modulate these anabolic and catabolic pathways, to modulate antiretroviral efficacy and toxicity. Importantly, NRTIs can impair mitochondrial function and cell homeostasis without depleting mtDNA. Possible mechanisms could include the accumulation of oxidative lesions and mutations in mtDNA, drug-induced inhibition of the adenine nucleotide translocator, diverse effects on FAO enzymes and/or cofactors such as L-carnitine, and also genotoxic effects on nDNA. Some of these "mtDNA-unrelated" effects could disturb lipid homeostasis and participate to cell death in some tissues. Although it is still unclear why different nucleoside analogues tend to have different tissue-selective toxicities, and why some individuals may be more susceptible, recent data allow us to put forward some hypotheses.

Insulin-dependent diabetes mellitus is among the most common metabolic disorders in humans. It results from the graduate loss of function and progressive destruction of insulin-producing beta cells in the pancreatic islets of Langerhans. Several factors have been implicated in the pathogenesis of the disease, including host genetics, autoimmune responses and environmental factors. Viruses are among the environmental factors considered to play crucial role in the initiation and progression of the disease. Since the first data on virus-induced diabetes were reported, growing experimental evidence accumulated, showing that neurotropic viruses, members of different taxonomic groups, participate in the etiopathogenesis of insulin-dependent diabetes in both experimental animals and in humans. There are at least three mechanisms of virus-induced diabetes: (i) direct damage of pancreatic beta cells due to viral cytolytic infection, (ii) induction of proinflammatory cytokines secretion, and (iii) triggering of beta cell-specific autoimmune reactions. The data so far demonstrate that enteroviruses are the most frequent etiological agents of acquired insulin-dependent diabetes in humans. Thus, development of antivirals, inhibitors of enteroviral replication, is considered to be of major importance in the prevention and treatment of this disease. Chemoprophylaxis in individuals at higher risk of diabetes incidence might successfully prevent the onset of type 1 diabetes. The review of available chemotherapeutic agents points out several highly active compounds in experimental studies, first favorable data being obtained in clinical trials. Drug resistance is specified as the main obstacle limiting the development and application of effective chemotherapeutic agents convenient for enterovirus-induced diabetes mellitus prevention. Administration of antivirals in combination with suitable biological response modifiers could serve as a basis for elaboration of the most prospective strategy for prevention and treatment of acquired virus-induced diabetes.

Bacterial urinary tract infections (UTIs) are frequently found in the outpatient as well as in the nosocomial setting. The bacterial UTIs can be stratified into uncomplicated and complicated UTIs. In uncomplicated UTIs Escherichia coli is the leading organism, whereas in complicated UTIs the bacterial spectrum is much broader including Gramnegative and Gram-positive organisms. Therapy of uncomplicated UTIs is almost exclusively antibacterial, whereas in complicated UTIs the complicating factors have to be treated as well. Antibiotic resistance nowadays plays an important role in the treatment of uropathogens causing uncomplicated and complicated UTIs. Especially in nosocomially acquired complicated UTIs antibiotic resistance rates are increasing to levels where empiric treatment with orally available antibiotics becomes difficult. In recent years also uropathogens causing uncomplicated UTIs became more resistant to the antibiotic substances most frequently used for this indication. There are two predominant aims in the antimicrobial treatment of both uncomplicated and complicated UTIs: i.) rapid and effective response to therapy, prevention of complications and prevention of recurrence in the individual patient treated, and ii.) prevention of emergence of resistance to anti-infective agents in the microbial environment. Bacterial resistance mechanisms to antibiotics are nowadays better understood which helps to design derivatives and new substances that will hopefully be less susceptible for the emergence of resistance. Pharmacokinetic and pharmacodynamic parameters are increasingly used to improve dosing strategies of the current antiinfective agents, to predict efficacy in patients and to minimize emergence of resistance. For the treatment of UTIs, however, these instruments are not yet developed satisfactorily enough. New treatment strategies are also needed to maintain effective treatment of UTIs. The aim of this review is to highlight the current and to describe future treatment options for UTIs. The chemistry of current substance groups and its importance for the antiinfective spectrum and activity is explained. Pharmacokinetic/ pharmacodynamic models for UTIs are described and new treatment options to cope with antimicrobial resistance are discussed.