Resistance to macrolide, lincosamide, streptogramin, ketolide, and oxazolidinone antibiotics

Macrolides have enjoyed a resurgence as new derivatives and related compounds have come to market. These newer compounds have become important in the treatment of community-acquired pneumoniae and nontuberculosis-Mycobacterium diseases. In this review, the bacterial mechanisms of resistance to the macrolide, lincosamide, streptogramin, ketolide, and oxazolidinone antibiotics, the distribution of the various acquired genes that confer resistance, as well as mutations that have been identified in clinical and laboratory strains are examined.     

利奈唑胺C 环结构改造研究进展

首个唑烷酮类抗菌药利奈唑胺自2000 年上市以来,其耐药性问题日趋严重,开发新型唑烷酮类抗菌药物成为研究热点之一。综述了近年来对利奈唑胺C 环进行的结构改造及相关衍生物的研究进展,旨在为唑烷酮类抗菌药的深入研发提供参考。     

Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials

A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.     

Synthesis of novel oxazolidinone antimicrobial agents

The oxazolidinone class of antimicrobials represents a promising advance in the fight against resistant Gram-positive bacterial infections. Four novel oxazolidinone antimicrobial compounds, each containing a benzodioxin ring system, have been prepared. The general synthesis of each compound begins with the construction of a benzodioxin ring system containing a nitro substituent that ultimately becomes the nitrogen of the oxazolidinone ring. Three of the compounds utilize high yielding 'click chemistry' in their final step. The antimicrobial activities of the new oxazolidinones have been measured and the MIC against Staphylococcus aureus for one of the antimicrobials was determined to be 2-3 microg/mL, which is comparable to the well-known oxazolidinone, linezolid.     

Synthesis and antibacterial activity of 5-substituted oxazolidinones

A series of 5-substituted oxazolidinones with varying substitution at the 5-position of the oxazolidinone ring were synthesized and their in vitro antibacterial activity was evaluated. The compounds demonstrated potent to weak antibacterial activity. A novel compound (PH-027) demonstrated potent antibacterial activity, which is comparable to or better than those of linezolid and vancomycin against antibiotic-susceptible standard and clinically isolated resistant strains of gram-positive bacteria. Although the presence of the C-5-acetamidomethyl functionality at the C-5 position of the oxazolidinones has been widely claimed and reported as a structural requirement for optimal antimicrobial activity in the oxazolidinone class of compounds, our results from this work identified the C-5 triazole substitution as a new structural alternative for potent antibacterial activity in the oxazolidinone class.     

Ribosomal RNA is the target for oxazolidinones, a novel class of translational inhibitors.

Oxazolidinones are antibacterial agents that act primarily against gram-positive bacteria by inhibiting protein synthesis. The binding of oxazolidinones to 70S ribosomes from Escherichia coli was studied by both UV-induced cross-linking using an azido derivative of oxazolidinone and chemical footprinting using dimethyl sulphate. Oxazolidinone binding sites were found on both 30S and 50S subunits, rRNA being the only target. On 16S rRNA, an oxazolidinone footprint was found at A864 in the central domain. 23S rRNA residues involved in oxazolidinone binding were U2113, A2114, U2118, A2119, and C2153, all in domain V. This region is close to the binding site of protein L1 and of the 3' end of tRNA in the E site. The mechanism of action of oxazolidinones in vitro was examined in a purified translation system from E. coli using natural mRNA. The rate of elongation reaction of translation was decreased, most probably because of an inhibition of tRNA translocation, and the length of nascent peptide chains was strongly reduced. Both binding sites and mode of action of oxazolidinones are unique among the antibiotics known to act on the ribosome.     

Design and synthesis of new secretory phospholipase A2 inhibitor of a phospholipid analog

All stereoisomers of N-acyl-4,5-disubstituted oxazolidinone phospholipid analogs were synthesized by regio and stereoselective epoxide ring opening accompanied by introduction of an amino group. The (4R,5S)-derivative showed stronger inhibitory activity toward type II phospholipase A₂ than the 4-substituted oxazolidinone phospholipid analog previously reported.     

Cross-linking in the living cell locates the site of action of oxazolidinone antibiotics

Oxazolidinone antibiotics, an important new class of synthetic antibacterials, inhibit protein synthesis by interfering with ribosomal function. The exact site and mechanism of oxazolidinone action has not been elucidated. Although genetic data pointed to the ribosomal peptidyltransferase as the primary site of drug action, some biochemical studies conducted in vitro suggested interaction with different regions of the ribosome. These inconsistent observations obtained in vivo and in vitro have complicated the understanding of oxazolidinone action. To localize the site of oxazolidinone action in the living cell, we have cross-linked a photoactive drug analog to its target in intact, actively growing Staphylococcus aureus. The oxazolidinone cross-linked specifically to 23 S rRNA, tRNA, and two polypeptides. The site of cross-linking to 23 S rRNA was mapped to the universally conserved A-2602. Polypeptides cross-linked were the ribosomal protein L27, whose N terminus may reach the peptidyltransferase center, and LepA, a protein homologous to translation factors. Only ribosome-associated LepA, but not free protein, was cross-linked, indicating that LepA was cross-linked by the ribosome-bound antibiotic. The evidence suggests that a specific oxazolidinone binding site is formed in the translating ribosome in the immediate vicinity of the peptidyltransferase center.     

Oxazolidinone: search for highly potent antibacterial

A number of substituted piperazinyl oxazolidinone derivatives have been synthesized and their antibacterial activities were evaluated by MIC determination. A systematic SAR was carried out to get highly potent oxazolidinone derivatives.     

The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria

The oxazolidinones are one of the newest classes of antibiotics. They inhibit bacterial growth by interfering with protein synthesis. The mechanism of oxazolidinone action and the precise location of the drug binding site in the ribosome are unknown. We used a panel of photoreactive derivatives to identify the site of action of oxazolidinones in the ribosomes of bacterial and human cells. The in vivo crosslinking data were used to model the position of the oxazolidinone molecule within its binding site in the peptidyl transferase center (PTC). Oxazolidinones interact with the A site of the bacterial ribosome where they should interfere with the placement of the aminoacyl-tRNA. In human cells, oxazolidinones were crosslinked to rRNA in the PTC of mitochondrial, but not cytoplasmic, ribosomes. Interaction of oxazolidinones with the mitochondrial ribosomes provides a structural basis for the inhibition of mitochondrial protein synthesis, which is linked to clinical side effects associated with oxazolidinone therapy.     

Concise stereocontrolled routes to fumagillol,fumagillin, and TNP-470

A concise, diastereoselective synthesis of (+/-)-fumagillol (3) and formal, enantioselective syntheses of the potent angiogenesis inhibitors fumagillin (1) and TNP-470 (2) are reported. The origin of asymmetry is a highly diastereoselective Diels-Alder reaction using a diene with a chiral oxazolidinone auxiliary. The stereochemical course of a key conjugate addition reaction is controlled by the cup-shaped architecture of a cis-fused bicyclic enal. Other key steps include a facile hetero-Claisen rearrangement and a site-selective Sharpless epoxidation.     

Design,synthesis and biological evaluation of oxazolidinone-quinolone hybrids

Oxazolidinone-quinolone hybrids that combine the pharmacophores of a quinolone and an oxazolidinone were synthesised and shown to be active against a variety of resistant and susceptible Gram-positive and fastidious Gram-negative organisms. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens. The nature of the spacer greatly influences the antibacterial activity. The dual mode of action could be demonstrated for compounds having a piperazinyl spacer. Antibacterial activity was higher at acidic pH.     

Efficient asymmetric synthesis of (S)-2-ethylphenylpropanoic acid derivative,a selective agonist for human peroxisome proliferator-activated receptor alpha

An optically active phenylpropanoic acid derivative, a selective agonist for human peroxisome proliferator-activated receptor alpha, was efficiently prepared in high optical purity by using Evans chiral oxazolidinone technique as a key step.     

Synthesis and antibacterial activity of linezolid analogues

Several new compounds of oxazolidinone class were designed and synthesized referring to the structure-activity relationship studies and the synthesis of Linezolid, and their antibacterial activity was studied.     

Synthesis and structure-activity studies of novel benzocycloheptanone oxazolidinone antibacterial agents

We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.     

Parallel kinetic resolution of an oxazolidinone using a quasi-enantiomeric combination of [D,13C]-isotopomers of pentafluorophenyl 2-phenyl propionate

Parallel kinetic resolution of Evans' phenylglycine derived oxazolidinone using an equimolar combination of quasi-enantiomeric active esters (derived from [D,13C]-labeled 2-phenylpropionic acid) was achieved. The levels of stereocontrol were high, leading to products with predictable configurations.     

Synthesis and biological activity of novel oxazolidinones

A number of 5-substituted derivatives of Ranbezolid, a novel oxazolidinone were synthesized. Antibacterial activity of the compounds against a number of sensitive and resistant bacteria showed promising results.     

Synthesis and biological evaluation of benzazepine oxazolidinone antibacterials

Novel benzazepine oxazolidinone antibacterials were synthesized and evaluated against clinically relevant susceptible and resistant organisms. The effect of ring nitrogen position and N-substitution on antibacterial activity is examined.     

The effect of remote chirality on the antibacterial activity of indolinyl, tetrahydroquinolyl and dihydrobenzoxazinyl oxazolidinones

The oxazolidinones are promising agents for the treatment of infections caused by gram-positive bacteria, including multidrug-resistant strains. In ongoing studies we have discovered that a strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC's<0.5 microg/mL for the most potent congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of alpha-methylated indoline derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed.     

Biaryl isoxazolinone antibacterial agents

In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.