Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 6, Issue 4, 2007

Doxycycline is a semi-synthetic tetracycline, which was invented and clinically developed in the early 1960s. Doxycycline works by inhibiting protein synthesis and it is also bacteriostatic. Doxycycline is highly effective against all of the common pathogens that cause upper respiratory tract infections. Doxycycline is particularLY effective for the treatment of atypical pneumonia due to Mycoplasma, Chlamydia and Legionella. Recently, doxycycline has been reported to have a biological function apart from its antimicrobial function. Doxycycline is known to inhibit the release of reactive oxygen species, while also inducing apoptosis, decreasing neutrophil chemotaxis and inhibiting matrix metalloproteinases. Regarding animal models, doxycycline is able to attenuate lung inflammation caused by several agents. Recently, several clinical trials using doxycycline have also been reported. In this review, we provide a comprehensive, yet concise analysis of the two different functions of doxycycline, while particularly focusing on respiratory diseases.

Legionella spp have been identified in many series as responsible for a variable percentage of communityacquired pneumonia (CAP) and for some outbreaks of hospital-acquired pneumonia (HAP). In many geographic areas Legionella ranks second to pneumococcus on the list of causes of severe CAP (SCAP). Therapeutic approach remains an important goal since the case-fatality rate is 5% to 30%, with elderly and immunocompromised patients at greatest risk of death. Clinicians should be aware of either dual or mixed infections and extrapulmonary localizations of Legionella since mortality may increase if these features continue unrecognized. Optimal therapy against Legionella infection is based on agents with high intrinsic activity, an appropriate pharmacokinetic and pharmacodynamic profile, including the ability to penetrate phagocytic cells, results of clinical studies, a low incidence of adverse reactions and an advantageous costefficacy relationship. Macrolides and fluoroquinolones are the first-line therapy. Azithromycin and clarithromycin present a better pharmacokinetic profile than erythromycin. The more recent fluoroquinolones, such as gemifloxacin or moxifloxacin generally show a better intrinsic activity than the older ones but the clinical relevance of that data is unclear since most patients with Legionnaires' disease show a positive outcome when an early administration of any effective anti- Legionella agent is indicated. Doxycycline also demonstrates a good intrinsic activity against Legionella. Recently marketed or under investigation anti-Legionella agents are ketolides (telithromycin or cethromycin), new fluorquinolones (garenoxacin, olamufloxacin, ABT-492, DW 286a), glycyclynes (tygecycline) and everninomycins (ziracin). Although these new therapeutic agents might be effective in treating pneumonia caused by Legionella, clinical experience of them is still quite limited. Combined therapy of rifampicin with macrolides or quinolones is still a controversial issue.

The emergence of nosocomial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) has prompted research directed at the development of novel antibacterial agents to treat these diseases. This review will examine the literature on anti-MRSA and anti-VRE antibacterial research published between 2001 and October 2006.

Entry of enveloped viruses into cells is initiated by virus binding to a target cell receptor. Subsequent conformational changes in the viral envelope proteins are triggered either by receptor binding or by the low pH of the endosome, depending on the virus family, and facilitate fusion, or merging of the viral and host cell membranes. This allows transfer of the viral genome into the target cell, initiating a new infectious cycle. Inhibitors of viral entry constitute a novel class of antivirals that target discrete steps of this process. Although long-studied for their antiviral potential, entry inhibitors have only recently been brought to market with the licensing of the first-in-class HIV fusion inhibitor T-20 (enfuvirtide, Fuzeon). Entry inhibitors are currently in development against major human and animal pathogens such as HIV, SARS coronavirus, and members of the paramyxovirus family including, amongst others, measles, respiratory syncytial virus (RSV), and Nipah virus. This antiviral class includes antibodies, peptides, and non-peptidic small molecules that act on different steps of the entry process. This review will concentrate on peptidic and non-peptidic inhibitors of viral entry, and describe their mechanisms of action and current development status. Particular emphasis will be given to the development of peptidic and small molecule inhibitors of membrane fusion.

This review describes the novel experimental observations on antimicrobial and antiviral activities of a synthetic killer peptide (KP), derived from the variable region of a recombinant antiidiotypic antibody mimicking a widespectrum microbicidal yeast killer toxin (KT). The rationale, generation and experimental use of KT-like antiidiotypic microbicidal antibodies and mimotopes against the opportunistic pathogen Candida albicans were previously discussed. Recently, KP has demonstrated an in vitro microbicidal activity against such diverse AIDS-related pathogens as Cryptococcus neoformans, Pneumocystis carinii, Paracoccidioides brasiliensis, Acanthamoeba castellanii, Leishmania major and L. infantum, Mycobacterium tuberculosis and other bacteria. KP also demonstrated a significant therapeutic effect against experimental vaginal and systemic candidiasis, disseminated cryptococcosis, and paracoccidioidomycosis. The observation that KP may inhibit ex-vivo HIV-1 replication, opens new perspectives in the simultaneous treatment of HIV-1 and AIDS-related opportunistic pathogens. Despite the advent of highly active antiretroviral therapy (HAART) has dramatically improved the prognosis and quality of life of HIV-infected people, opportunistic infections still remain the most common cause of death. Current combination regimens, moreover, remain hampered by issues of patient compliance, tolerance, long term toxicity, incomplete viral suppression, and drug resistance, which are often responsible for therapy failure. There is an urgent need for new therapeutic strategies in AIDS. The potential use of KP, endowed with minimal toxicity, ease of production and manipulation (such as its production in planta), differential antimicrobial and antiviral mechanism of action, and modulation of immune cell populations are discussed.

The thiazolide nitazoxanide (2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide; NTZ) is a compound that has been synthesized based on the structures of niclosamide (antihelminthic) and metronidazole (anti-anaerobic). It is essentially composed of a nitrothiazole-ring and a salicylic acid moiety, which are linked together through an amide bond. NTZ exhibits a broad spectrum of activities against a wide range of intestinal and tissue-dwelling helminths, protozoa, and enteric bacteria infecting animals and humans. The drug has been postulated to act via reduction of its nitro-group by nitroreductases including pyruvate ferredoxin oxidoreductase (PFOR), which would then generate a toxic radical that could have anti-parasitic and anti-bacterial activities. However, experimental evidence for this mode of action is lacking. Instead, the drug has been shown to inhibit the functional activity of PFOR in several extracellular anaerobic organisms, but the activity against intracellular pathogens appears to be based on (an)other mechanism(s) of action. Since the first synthesis of the drug, a number of derivatives of NTZ have been produced, which are collectively named thiazolides. These are modified versions of NTZ, which include the replacement of the nitro-thiazole with other functional groups, and the differential positioning of methyl- and methoxy-groups on the salicylate ring. Investigations on the activities of these thiazolides were carried out by studying morphological and ultrastructural changes upon drug treatments, by defining physiological alterations, and by applying biochemical and genetic approaches to identify respective targets and the molecular basis of resistance formation. Collectively, these studies strongly suggest that NTZ and other thiazolides exhibit multiple mechanisms of action, targeting differential metabolic pathways, and each acting specifically against intracellular and extracellular pathogens, respectively. This could explain the broad range of activities (anti-parasitic, anti-bacterial and antiviral) of the thiazolide class.