Section Reviews; Anti-infectives: Section Review Anti-infectives: Quinolone antibacterials and derivatives as antineoplastic agents

4-quinolone antibacterials represent a new class of potent, safe therapeutants to combat bacterial infections. The qualities that render quinolones so effective in therapy-potency, specificity, pharmacokinetics, bioavailability - are the same qualities that also make quinolones an interesting class of potential antitumour agents. From the initial discovery of the activity of several newer quinolones as potent mammalian topoisomerase II inhibitors, numerous laboratories have worked to identify and develop quinolones as antitumour agents. Whilst no single candidate has yet advanced into later stage clinical trials, there remains intense interest in this class. Quinolones may represent a future cytotoxic therapeutic class of antitumour drugs if issues related to toxicity and therapeutic index are resolved. Laboratory examination indicates that numerous quinolone and quinolone-related series have met or surpassed the intrinsic potency of antitumour agents currently in clinical usage.     

Section Review Anti-infectives: Azole antifungal agents

Azole antifungal agents are used extensively throughout the world due to their excellent antifungal activity and low toxicity. However, improvements are needed in their spectra, potency and pharmaco-kinetic properties. Current research efforts are being directed towards overcoming these problems through the development of new, improved azole compounds. This article describes recent advances in the development of azole antifungal agents following on from fluconazole (FLCZ) and itraconazole (ITCZ).     

Section Review: Anti-infectives: Lipopeptide antifungal agents

There is a need for safe and effective antifungal agents due to the rise in the immunocompromised patient population. Lipopeptides are an emerging class of antifungal agents. Two structural classes, the aureobasidins and echinocandins are discussed. The aureobasidins are cyclic lipodepsipeptides with an unknown mode of action. Although aureobasidin A possesses in vitro activity against Candida and Cryptococcus and is orally bioavailable, in vivo studies suggest that it is a Candida-only agent with the potential for activity against blastomycosis and histoplasmosis. Lipopeptides, represented by the echinocandin cyclic hexapeptides, are cidal agents which inhibit the synthesis of β-(1,3)-glucan. Fujisawa has disclosed FR901379, a lipopeptide that possesses intrinsic water solubility, suitable for parenteral administration, but is less potent than compounds disclosed by Lilly or Merck. Lilly has disclosed a phosphate ester prodrug, LY307853, with water solubility, usable oral bioavailability, potent Candida, Histoplasma, Aspergillus and Pneumocystis activities and good pharmacokinetics. The parent compound, LY303366, a pentyloxyterphenyl side chain derivative of echinocandin B, is reportedly identical to the phosphate in all aspects except aqueous solubility. Merck has disclosed a series of water soluble amine-bearing pneumocandin derivatives, L-705,589, L-731,373 and L-733,560, with good activity against Candida, Aspergillus and Pneumocystis. The combination analogue, L-733,560, shows good potency and primate pharmacokinetics.     

Section Review: Anti-infectives: The value of steroids in the treatment of herpes zoster

Since 1951 short courses of systemic corticosteroids have been used widely in the treatment of acute herpes zoster with the predominant aims of decreasing the severity of the acute illness and preventing or shortening the duration of post-herpetic neuralgia. This practice has not been based upon well designed studies of adequate size. A large well-controlled study of corticosteroid use has recently been reported and, in conjunction with previous smaller controlled trials, enables a critical evaluation of this therapy. We conclude that there is no evidence that systemic corticosteroids given early in acute herpes zoster are beneficial in preventing or shortening the period of post-herpetic neuralgia but that there is a short-lived reduction in the severity of acute pain when steroids and acyclovir are given in combination. However, owing to the risk of side effects, we believe this small gain is insufficient to justify the routine use of steroids in this illness.     

Section Review Anti-infectives: The future role of quinolones

Quinolones, such as ciprofloxacin and ofloxacin, have gained wide acceptance for the treatment of bacterial infections of the respiratory tract, urinary tract, skin and soft tissues, as well as sexually transmitted diseases. Good pharmacokinetic profiles and potent activities against a wide range of Gram-negative and Gram-positive pathogens result in the use of these antibacterials in both hospital and community settings. Although recently developed clinical quinolones dominate in the chemotherapy of various bacterial infections, their use is restricted by limited activities against a number of clinically-important Gram-positive bacteria such as Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and enterococci. Ciprofloxacin, the market leader, also has low potency against anaerobes. Bacterial resistance (such as in Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus) to ciprofloxacin is increasing rapidly. Many quinolone compounds are being synthesised to address these drawbacks. The new quinolones currently under development are characterised by enhanced activities against streptococci, staphylococci, enterococci and anaerobes. Although the treatment of traditional bacterial infections is at present the focus of quinolone research, the future role of quinolones will extend current applications to include new indications of bacterial infections and other non-bacterial diseases. This review will concentrate on the more recently developed quinolones which possess significantly more therapeutic value than existing quinolones, and will provide information on those compounds under commercial development with major therapeutic potential. Recent developments in research into the identification of quinolones for the treatment of tuberculous, cancer, viral, fungal infections and parasitic diseases will also be discussed.     

Section Review Anti-infectives: Current perspectives on the treatment and prevention of hepatitis C infection

Hepatitis C virus (HCV) is thought to infect 0.5 - 1.5% of the world's population. In the majority of cases the infection is chronic, and in at least 20% hepatic cirrhosis develops within 20 years representing a major public health problem for the 1990s. Effective treatment is of paramount importance. Therapy for chronic HCV infection has been developed either to improve the host's immune response or to prevent virus replication. Presently the only licensed compound for treatment of HCV infection is alpha-interferon. Analysis of controlled trials of alpha-interferon therapy has identified that a sustained response occurs in less than 25% of patients treated. There are, however, several host and viral factors that are known to affect the efficacy of interferon therapy. It is likely that future treatment regimens will incorporate combinations of compounds with different modes of action. This review article examines regimens to improve the efficacy of alpha-interferon therapy, current treatment options available, the spectrum of drugs under development and the search for an effective vaccine.     

Section Review Anti-infectives: Developments in viral hepatitis during 1995

The discovery of hepatitis C virus (HCV) in 1987 and the subsequent development of diagnostic tests has accounted for the majority of cases of viral hepatitis throughout the world. However, a significant number of cases cannot be assigned to any of the viral hepatitis groups (A - E). During 1995 two companies reported the identification of novel hepatitis viruses known as GBV-B and hepatitis G virus (HGV), which were found to be responsible for a large proportion of the remaining undiagnosed cases. Sequence analysis of these two viruses revealed them to be isolates of the same virus and, moreover, to be close homologues of HCV. The clinical significance of these new viruses is currently unclear, but preliminary epidemiologic evidence suggests they are often found as co-infections with HCV. The close similarity of these viruses to HCV and the fact that related viruses have also been identified which infect small primates, suggests that they may be useful as surrogate agents for the identification of novel therapeutic agents against HCV. Current therapeutic agents against HCV are still disappointing although more encouraging data have been reported on long-term combination therapy with interferon-′ and ribavirin. Studies have continued aimed towards developing assays for biochemical functions specified by viral proteins and these are stili mainly focused on the multi-functional NS3 protein.     

Section Reviews; Anti-infectives: Section Review Anti-infectives: Natural mediators of host-defence: The role of H2O2 in the regulation of bacteriostasis

Host-defence against many different pathogenic microorganisms in higher life forms is mediated in part by the production of reactive oxygen species (ROS) generated by a variety of different cellular mechanisms. Since ROS are highly toxic to all living cells, it is important to understand how ROS are used specifically by higher organisms to eliminate pathogens, without causing undue tissue damage to the host. Total elimination of the pathogen clearly involves complete killing, and is generally referred to in this review in general terms as a ‘bactericidal’ process (although not all pathogens eliminated by these mechanisms are necessarily bacteria). However, killing of microorganisms by mechanisms involving ROS must be carefully compartmentalised to avoid injury to the host. Other mechanisms of controlling pathogens may involve processes that inhibit the growth of the pathogen. This effect on invading pathogens is referred to as ‘bacteriostasis’, (again, this process is not necessarily limited to just bacteria). In this review, some of these issues will be reviewed, with special reference to H₂O₂ produced in the extracellular fluid. This oxidant may have a special role in host defence, in that it inhibits cell division at relatively low concentrations (< 50 μM), without causing cellular toxicity. The experimental evidence that this mechanism plays a central role in host defence will be reviewed.     

Section Review Anti-infectives: Recent advances in anti-hepatitis B virus agents

In recent years, deaths related to hepatitis B virus (HBV) infection and the closely associated hepatocarcinoma, greatly outweigh those occuring as a result of human immunodeficiency virus (HIV) infection, a fact that may hold true for the next five to ten years. With a similar route of infection, HBV and HIV may co-spread and prove difficult to confine to a specific group of people. Many potent anti-HBV agents have also been found to be very effective against HIV, such as 3TC ((-)SddC), (-)FSddC, D4T and ddl, indicating that there might be subtle similarities between these two distinct classes of viruses. Therefore, discovery of a potent anti-HBV agent could sometimes also mean discovery of a potential anti-HIV agent, or vice versa. This may be particularly true as more and more L-nucleosides are evaluated. In this review article we have covered most of the existing approaches, and aim to provide sufficient up-to-date information for interested scientists to further advance anti-HBV research.     

Section Review: Anti-infectives: The potential of novel antifungal drugs for the treatment of disease in the immunocompromised host

There is a growing need for new antifungal drugs to complement those already in clinical use. Analogues and new formulations of existing drugs continue to give improvements in chemotherapy, but this account concentrates on possible new areas of development. These have been inspired chiefly by results from screening for new natural products. The most promising are three groups of antibiotics targeting the fungal cell walls. The echinocandins and related lipopeptides and their semisynthetic derivatives, and the papulacandin glycolipids are potent specific inhibitors of β-(1–3)-glucan synthesis. Pradimicins and benanomicins bind to mannan in the cell wall, but then target the cell membrane, disrupting its function. A wide range of other novel antifungal natural products, some with very unusual structures, are currently under critical investigation. The possible selective antifungal activity of members of the families of immunosuppressive drugs, cyclosporins and rapamycins, is worthy of further study. In a different approach, much current research in the metabolism and molecular biology of pathogenic fungi is directed ultimately at rational design of specific antifungal agents, but at present this is a hope for the future.     

Anti-infectives: New technologies

A selection of World Wide Web sites relevant to papers published in this issue of Current Opinion in Pharmacology.     

Anti-infectives: New technologies

A selection of World Wide Web sites relevant to papers published in this issue of Current Opinion in Pharmacology.     

New approaches to the prevention and treatment of severe S. aureus infections

Staphylococcus aureus is a virulent pathogen that is currently a major cause of community-acquired infections, as well as infections in hospitalized patients. Morbidity and mortality due to S. aureus infections, such as sepsis, osteomyelitis, septic arthritis and infective endocarditis, remain high despite the use of newer antibiotics. Of major concern, methicillin resistance in S. aureus isolates has increased dramatically worldwide, especially among nosocomial isolates; this phenotype may be associated with resistance to other antistaphylococcal compounds, including vancomycin. This increase in prevalence of multiantibiotic resistance in S. aureus is a major public health concern. Currently, there is an intense focus on the development of novel vaccines for the prevention of S. aureus infections in high-risk populations and on new antimicrobial classes for the therapy of established S. aureus infections.     

Novel approaches to developing new antibiotics for bacterial infections

Antibiotics are an essential part of modern medicine. The emergence of antibiotic-resistant mutants among bacteria is seemingly inevitable, and results, within a few decades, in decreased efficacy and withdrawal of the antibiotic from widespread usage. The traditional answer to this problem has been to introduce new antibiotics that kill the resistant mutants. Unfortunately, after more than 50 years of success, the pharmaceutical industry is now producing too few antibiotics, particularly against Gram-negative organisms, to replace antibiotics that are no longer effective for many types of infection. This paper reviews possible new ways to discover novel antibiotics. The genomics route has proven to be target rich, but has not led to the introduction of a marketed antibiotic as yet. Non-culturable bacteria may be an alternative source of new antibiotics. Bacteriophages have been shown to be antibacterial in animals, and may find use in specific infectious diseases. Developing new antibiotics that target non-multiplying bacteria is another approach that may lead to drugs that reduce the emergence of antibiotic resistance and increase patient compliance by shortening the duration of antibiotic therapy. These new discovery routes have given rise to compounds that are in preclinical development, but, with one exception, have not yet entered clinical trials. For the time being, the majority of new antibiotics that reach the marketplace are likely to be structural analogues of existing families of antibiotics or new compounds, both natural and non-natural which are screened in a conventional way against live multiplying bacteria.     

Review: Anti-infectives Novel mitomycin derivatives

Modification studies describing the synthesis of a number of mitomycin derivatives that have appeared in the patent literature during recent years are reviewed. Particular emphasis is placed on the design of the derivatives and their preparation. Biological activities, reaction schemes and structure-activity relationships for the derivatives are also mentioned in this review.     

New ways to treat bacterial infections

There is an urgent need for fresh approaches to the treatment of bacterial infections because of the changing patterns of infectious disease and the emergence of bacterial strains resistant to current antibiotics. Modification of the cell phenotype to sensitize bacteria to components of the hosts' immune system or to previously ineffective antibiotics could prevent the emergence of the resistant genotype. In addition, the use of light-activated antibacterial agents and lytic bacteriophage specific for key pathogens should be considered as safe and inexpensive alternatives to conventional treatment regimens for certain non-systemic infections.