Isolation, Structure, and Antibacterial Activity of Philipimycin, A Thiazolyl Peptide Discovered from Actinoplanes philippinensis MA7347 (original) (raw)
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Journal of Natural Products, 2009
Ribosomal protein S4 (RPSD), a part of the ribosomal small subunit, is one of the proteins that is a part of the ribosomal machinery and is a potential new target for the discovery of antibacterial agents. Continued screening of microbial extracts using antisense-sensitized rpsD Staphylococcus aureus strain led to the isolation of a new dimeric compound, phaeosphenone (2). Compound 2 showed broad-spectrum antibacterial activity against Gram-positive bacteria, exhibiting MIC values ranging from 8 to 64 µg/mL. Phaeosphenone showed the highest sensitivity for Streptococcus pneumoniae (8 µg/mL) and inhibited the growth of Candida albicans with an MIC of 8 µg/mL. Phaeosphenone showed a modest selectivity for the inhibition of RNA synthesis over DNA and protein synthesis in S. aureus.
Ribosomal Antibiotics: Contemporary Challenges
Most ribosomal antibiotics obstruct distinct ribosomal functions. In selected cases, in addition to paralyzing vital ribosomal tasks, some ribosomal antibiotics are involved in cellular regulation. Owing to the global rapid increase in the appearance of multi-drug resistance in pathogenic bacterial strains, and to the extremely slow progress in developing new antibiotics worldwide, it seems that, in addition to the traditional attempts at improving current antibiotics and the intensive screening for additional natural compounds, this field should undergo substantial conceptual revision. Here, we highlight several contemporary issues, including challenging the common preference of broad-range antibiotics; the marginal attention to alterations in the microbiome population resulting from antibiotics usage, and the insufficient awareness of ecological and environmental aspects of antibiotics usage. We also highlight recent advances in the identification of species-specific structural motifs that may be exploited for the design and the creation of novel, environmental friendly, degradable, antibiotic types, with a better distinction between pathogens and useful bacterial species in the microbiome. Thus, these studies are leading towards the design of " pathogen-specific antibiotics, " in contrast to the current preference of broad range antibiotics, partially because it requires significant efforts in speeding up the discovery of the unique species motifs as well as the clinical pathogen identification.
Bioorganic & Medicinal Chemistry, 2009
Protein synthesis is one of the best antibacterial targets that have led to the development of a number of highly successful clinical drugs. Protein synthesis is catalyzed by ribosome, which is comprised of a number of ribosomal proteins that help the catalysis process. Ribosomal protein S4 (RPSD) is one of the proteins that is a part of the ribosomal machinery and is a potential new target for the discovery of antibacterial agents. Screening of microbial extracts usingantisense-sensitized rpsD Staphylococcus aureus strain led to the isolation of pleosporone, a new compound, with modest antibacterial activities with MIC ranging from 1 to 64 lg/ mL. This compound showed the highest sensitivity for Streptococcus pneumoniae and Haemophilus influenzae, and exhibited MIC's of 4 and 1 lg/mL, respectively. Pleosporone showed modest selectivity for the inhibition of RNA synthesis compared to DNA and protein synthesis, and showed activity against HeLa cells. Isolation, structure elucidation, and biological activity of pleosporone have been described.
Journal of Antibiotics, 2009
Protein synthesis inhibition is a highly successful target for developing clinically effective and safe antibiotics. There are several targets within the ribosomal machinery, and small ribosomal protein S4 (RPSD) is one of the newer targets. Screening of microbial extracts using antisense-sensitized rpsD Staphylococcus aureus strain led to isolation of okilactomycin and four new congeners from Streptomyces scabrisporus. The major compound, okilactomycin, was the most active, with a minimum detection concentration of 3-12 lg ml À1 against antisense assay, and showed an MIC of 4-16 lg ml À1 against Gram-positive bacteria, including S. aureus. The congeners were significantly less active in all assays, and all compounds showed a slight preferential inhibition of RNA synthesis over DNA and protein synthesis. Antisense technology, due to increased sensitivity, continues to yield new, even though weakly active, antibiotics.
From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials
Antibiotics, 2016
Macrolides, as a class of natural or semisynthetic products, express their antibacterial activity primarily by reversible binding to the bacterial 50S ribosomal subunits and by blocking nascent proteins' progression through their exit tunnel in bacterial protein biosynthesis. Generally considered to be bacteriostatic, they may also be bactericidal at higher doses. The discovery of azithromycin from the class of macrolides, as one of the most important new drugs of the 20th century, is presented as an example of a rational medicinal chemistry approach to drug design, applying classical structure-activity relationship that will illustrate an impressive drug discovery success story. However, the microorganisms have developed several mechanisms to acquire resistance to antibiotics, including macrolide antibiotics. The primary mechanism for acquiring bacterial resistance to macrolides is a mutation of one or more nucleotides from the binding site. Although azithromycin is reported to show different, two-step process of the inhibition of ribosome function of some species, more detailed elaboration of that specific mode of action is needed. New macrocyclic derivatives, which could be more potent and less prone to escape bacterial resistance mechanisms, are also continuously evaluated. A novel class of antibiotic compounds-macrolones, which are derived from macrolides and comprise macrocyclic moiety, linker, and either free or esterified quinolone 3-carboxylic group, show excellent antibacterial potency towards key erythromycin-resistant Gram-positive and Gram-negative bacterial strains, with possibly decreased potential of bacterial resistance to macrolides.
Structural Basis for the Antibiotic Activity of Ketolides and Azalides
Structure, 2003
Max-Planck-Research Unit cations, leading to antibiotic-resistant microorganisms, have been identified (reviewed in [4, 5]). for Ribosomal Structure 22603 Hamburg The rapid emergence of drug resistance in many pathogenic bacteria intensified the search for new anti-Germany 2 Weizmann Institute microbial agents, which led to the development of chemically modified macrolides, namely, the azalides [6] and 76100 Rehovot Israel ketolides [7]. Azalide antimicrobials are semisynthetic derivatives of erythromycin with a 15-membered lactone 3 Max-Planck-Institute for Molecular Genetics 14195 Berlin ring . The insertion of a methyl-substituted nitrogen in the lactone ring increases the basicity, re-Germany sulting in improved acid stability and bioavailability compared with erythromycin. Ketolides are a novel class of antibiotics derived from 14-membered macrolides by Summary substitution of the cladinose sugar by a 3-keto group ( ). The azalide azithromycin and the ketolide ABT-773, which were derived by chemical modifications of In gram-negative bacteria, resistance to macrolides is frequently related to the impermeability of the cellular erythromycin, exhibit elevated activity against a number of penicillin-and macrolide-resistant pathogenic outer membrane because of the hydrophobic nature of macrolides [8-10]. Clinically acquired resistance to bacteria. Analysis of the crystal structures of the large ribosomal subunit from Deinococcus radiodurans com-macrolides is mostly due to the production of methylases by a group of genes termed the erm genes. Azithro-plexed with azithromycin or ABT-773 indicates that, despite differences in the number and nature of their mycin and ABT-773 were designed to overcome these obstacles and were found to yield a higher efficiency contacts with the ribosome, both compounds exert their antimicrobial activity by blocking the protein exit against some gram-negative respiratory pathogens, such as Haemophilus influenzae and enteric bacilli, in-tunnel. In contrast to all macrolides studied so far, two molecules of azithromycin bind simultaneously to the cluding Shigella and Salmonella species [11-13]. Azithromycin has the additional advantage of prolonged tunnel. The additional molecule also interacts with two proteins, L4 and L22, implicated in macrolide resis-tissue levels, offering short treatment regimes and improved tolerance [14]. The induction of the production tance. These studies illuminated and rationalized the enhanced activity of the drugs against specific macro-of the methylases is, furthermore, suppressed for macrolides like josamycin [15, 16] and ketolides like ABT-lide-resistant bacteria.
Synthesis, antibacterial action, and ribosome inhibition of deoxyspectinomycins
The Journal of Antibiotics, 2021
Spectinomycin, an aminocyclitol antibiotic, is subject to inactivation by aminoglycoside modifying enzymes (AMEs) through adenylylation or phosphorylation of the 6-hydroxy group position. In this study, the effects of deoxygenation of the 2- and 6-hydroxy group positions on the spectinomycin actinamine ring are probed to evaluate their relationship to ribosomal binding and the antimicrobial activities of spectinomycin, semisynthetic aminomethyl spectinomycins (amSPCs), and spectinamides. To generate these analogs, an improved synthesis of 6-deoxyspectinomycin was developed using the Barton deoxygenation reaction. 6-Dehydrospectinamide was also synthesized from spectinamide 4 to evaluate the H-bond acceptor character on the C-6 position. All the synthesized analogs were tested for antibacterial activity against a panel of Gram (+) and Gram (−) pathogens, plus Mycobacterium tuberculosis. The molecular contribution of the 2- and 6-hydroxy group and the aryl functionalities of all analo...