Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 6, Issue 2, 2007

Melioidosis is caused by the gram-negative bacterium Burkholderia pseudomallei. The disease can present with a diverse range of clinical manifestations and is endemic in northern Australia and Southeast Asia. There is a dramatic increase in clinical cases during the wet season and mortality rates remain as high as 70% in some endemic areas. This is despite current optimal treatment with ceftazidime or meropenem, with trimethoprim-sulfamethoxazole.. This highlights the need for studies into novel antimicrobials or adjunctive therapies. There are currently no CLSI disc diffusion susceptibility criteria for this organism. A comparative study looking at methods of susceptibility testing for B. pseudomallei showed that an MIC based method is required to test susceptibility against trimethoprim-sulfamethoxazole. CLSI MIC breakpoints for this organism are available. In-vitro susceptibility testing to alternative antimicrobials has also been done for ertapenem, moxifloxacin and tigecycline. Recently, a BALB/c mouse model of melioidosis has been used to investigate strategies for antimicrobial therapy. Combination therapy with ceftazidime and trimethoprim-sulfamethoxazole has been found to be most efficacious. The use of granulocyte colony stimulating factor as adjunctive therapy has also been studied and shown to be of little value in this model. Similar studies are planned for the novel glycylcycline tigecycline. An Acanthamoeba intracellular, broth microdilution, model for B. pseudomallei has also been developed. This showed elevated MICs to both meropenem and ceftazidime when compared with standard MIC determination. Both these alternative models provide us with a unique opportunity to further our knowledge in several key aspects of an important tropical infectious disease.

The ultimate goal of proteome research is the comprehensive description of all proteins present in a given sample using qualitative, quantitative and functional metrics. Traditionally, protein mixtures were first separated by twodimensional gel electrophoresis and spots of interest were excised, in-gel digested and analyzed by mass spectrometry (MS). In most cases, protein identification was done by MALDI-TOF-MS (matrix-assisted laser desorption/ionization time-of-flight). The methodology is time consuming and rarely leads to a comprehensive description of the analyzed proteome. Over the last years shot-gun expression profiling methodologies were developed and can identify thousands of proteins in complex biological samples in a single experiment. We will provide a short historic overview of proteome research and mass spectrometry technologies currently used in the systems biology community. In particular, we will summarize the developments and applications of shot-gun proteomics and allied computational data mining tools to medical research and infectious disease research.

Aminoglycosides are aminoglycosidic aminocyclitols that contain amino sugars linked to an aminocyclitol ring by glycosidic bonds. Although relatively toxic compared with other classes of antibiotics, they remain primarily useful drugs in the treatment of infections caused by gram-negative bacteria. Since the advent of streptomycin by Waksman and co-workers, a series of milestone compounds like kanamycin, gentamicin, and tobramycin were introduced for the treatment of gram-negative bacillary infections. In 1970s, the semisynthetic aminoglycosides dibekacin, amikacin, and netilmicin demonstrated the possibility of obtaining compounds active against resistant strains that had developed resistance mechanisms towards earlier aminoglycosides. However, since then, the pace of development of new aminoglycosides has markedly slowed down. This review not only provides the comprehensive accounts of the developments in aminoglycoside antibiotics, but also provides insight about the mechanism of action and resistance, current efforts to develop aminoglycoside mimetics that target RNA, and potential strategies to overcome inactivation of aminoglycosides by aminoglycoside- modifying enzymes. Some of the interesting clinical implications like natural aminoglycoside resistances typical of common pathogens, prediction of responsible aminoglycoside-modifying enzyme from antibiogram data, and the use of liposomal-encapsulated aminoglycosides to increase the therapeutic index have also been discussed.

The worldwide rise in antibiotic resistance by microorganisms has stimulated intensive research toward the development of alternative therapeutic strategies. Photodynamic therapy (PDT) is emerging as a promising modality for the treatment of localized microbial infections. Studies on the relationship between the chemical structure of photosensitising agents and their phototoxicity against microbial pathogens led to the identification of a selected number of compounds with optimal cytocidal effects. These include phenothiazine, porphyrin and phthalocyanine derivatives, whose molecule has been engineered to introduce the following features: (a) presence of cationic moieties, preferably due to quaternarized amino groups; (b) introduction of at least one N-alkyl group having a relatively long hydrocarbon chain; (c) overall amphiphilic character to promote the partitioning in the plasma membrane. Studies on cell cultures indicate that PDT is endowed with favourable properties to act as an antimicrobial modality: (a) broad spectrum of action, since one irradiation protocol can be used to obtain the inactivation of different groups of pathogens, such as Gram-positive and Gram-negative bacteria, yeasts, mycoplasmas and protozoa in both vegetative and cystic stages; (b) fast association with microbial cells, which allows irradiations to be performed after incubation times as short as 5-10 min., thereby guaranteeing a high selectivity as compared with host tissues; (d) high photoinactivation efficiency, since a 5-6 log decrease in microbial population is obtained by irradiation under mild conditions; (e) photosensitising activity independent of the antibiotic-resistance spectrum of the given pathogen; (f) lack of selection of photoresistant strains upon repeated treatment and minimal risk to induce the onset of mutagenic processes. Initial clinical trials involve the treatment of chronic ulcers and selected oral infections.

Lincomycin and its derivatives are antibiotics exhibiting biological activity against bacteria, especially Grampositive ones, and also protozoans. Lincomycin and its semi-synthetic chlorinated derivative clindamycin are widely used in clinical practice. Both antibiotics are bacteriostatic, inhibiting protein synthesis in sensitive bacteria, and they may even be bactericidal at higher concentrations that can still be reached in vivo. Clindamycin is usually more active than lincomycin in the treatment of bacterial infections, in particular those caused by anaerobic species; it can also be used for the treatment of important protozoal diseases, e.g. malaria, most effectively in combination with other antibiotic or nonantibiotic antimicrobials (primaquine, fosfidomycin, benzoyl peroxide). Resistance to lincomycin and clindamycin may be caused by methylation of 23S ribosomal RNA, modification of the antibiotics by specific enzymes or active efflux from the bacterial cell. In addition to the various medicinal applications and modes of microbial resistance to lincosamides, the review describes the chemical structures of lincosamide antibiotics and analytical procedures used for identification, separation and isolation of these compounds and their metabolites. The biosynthesis of lincomycin and related compounds and its genetic control are also briefly discussed.

The formation and spread of infections by multi-resistant bacteria is favoured by the absence of hygienic measures to prevent the spread in hospital settings as well as the frequent use of antibiotics. Overall, approximately 20% of Staphylococcus aureus isolates in Europe are reported as methicillin resistant and cause serious nosocomial infections. Therefore, the worldwide rise in antibiotic resistance in clinical practise has led to the search for alternative methods of selectively destroying pathogens without harming the host tissue. One “new” approach to treat microbial infections uses light in combination with a photosensitizer to induce a phototoxic reaction by reactive oxygen species similar as in photodynamic therapy of skin cancer. In particular, different classes of molecules including porphyrins, phthalocyanines, phenothiazine and fullerenes have demonstrated antimicrobial efficacy against a broad spectrum of multi-resistant bacteria upon irradiation with visible light. Another “new” approach is called bacteriophage therapy, which involves using phages or their products as bioactive agents for the prophylaxis and/or treatment of bacterial infectious diseases. Phages were used topically, orally or systemically and have demonstrated efficacy against Gram (-) bacteria, whereas purified phageencoded agents are also effective against Gram (+) bacteria.