In vitro activity of linezolid and eperezolid, two novel oxazolidinone antimicrobial agents, against anaerobic bacteria

Linezolid (formerly U-100766) and eperezolid (formerly U-100592) are novel oxazolidinone antimicrobial agents that are active against multi-drug-resistant staphylococci, streptococci, enterococci, corynebacteria, and mycobacteria. Preliminary studies also demonstrated that the compounds inhibited some test strains of anaerobic bacteria. Therefore, we extended the in vitro evaluation of these agents to include a total of 54 different anaerobic species. Minimal inhibitory concentration (MIC) values were determined using a standard agar dilution method for 143 anaerobic bacterial isolates. Eperezolid and linezolid demonstrated potent activity against the anaerobic Gram-positive organisms with most MIC values in the range of 0.25-4 microg/mL. Viridans streptococci demonstrated MICs of 1-2 microg/mL; Peptostreptococcus species and Propionibacterium species were inhibited by 相似文献   

Chloropyrimidines as a new class of antimicrobial agents

In the course of our investigations of pyrimidines as antimycotic agents, we have identified a sub-class, with significant in vitro activity against mycobacteria. The salient feature of these pyrimidine derivatives (3a-o and 7a,b) is their appended aryl, heteroaryl and alkylthio substituent at position 6 and also alkylthio substituent at position 2. The rational design, synthesis, and evaluation of the in vitro antibacterial activity against six pathogenic bacteria including virulent and non-virulent strains of Mycobacterium tuberculosis is described. Some of the synthesized compounds (3c, 3h, 3i, 3o) have displayed only potent in vitro antimycobacterial activity with MIC of 0.75 microg/mL except 3i which also demonstrated activity against Escherichia coli at 12.5 microg/mL concentration. Only two compounds, 3a and 3b, demonstrated antibacterial activity against Pseudomonas aeruginosa and E. coli with MIC 12.5 microg/mL. All the synthesized compounds were also evaluated for their antimycotic activity against five pathogenic fungi but only some of them 3j-n and 7a,b were found most potent against Aspergillus fumigatus and Trichophyton mentagrophytes.     

Optically active antifungal azoles: synthesis and antifungal activity of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazol-2-yl/1-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol

A series of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazol-2-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol (11a-n) and (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazole-1-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol (12a-n) has been synthesized. The antifungal activity of compounds was evaluated by in vitro agar diffusion and broth dilution assay. Compounds 11d and its positional isomer 12d having 3-trifluoromethyl substitution on the phenyl ring of piperazine demonstrated significant antifungal activity against variety of fungal cultures (Candida spp. C. neoformans and Aspergillus spp.). The compound 12d showed MIC value of 0.12 microg/mL for C. albicans, C. albicans V-01-191A-261 (resistant strain); 0.25 microg/mL for C. tropicalis, C. parapsilosis ATCC 22019 and C. krusei and MIC value of 0.5 microg/mL for C. glabrata, C. krusei ATCC 6258, which is comparable to itraconazole and better than fluconazole. Further, compound 11d showed significant activity (MIC; 0.25-0.5 microg/mL) against Candida spp. and strong anticryptococcal activity (MIC; 0.25 microg/mL) against C. neoformans.     

Complexes of 2-thiophenecarbonyl and isonicotinoyl hydrazones of 3-(N-methyl)isatin. A study of their antimicrobial activity

Cobalt(II), nickel(II), copper(II) and zinc(II) complexes of 2-thiophenecarbonyl and isonicotinoyl hydrazones of 3-(N-methyl)isatin (HL(1) and HL(2), respectively) were synthesized and characterized, being the crystal structures of HL(1), HL(2) and [Ni(L(1))(2)].2CHCl(3) elucidated by X-ray diffraction techniques. The in vitro antimicrobial activity of all these compounds was tested against several bacteria and fungi. HL(1)and its complexes exhibited a strong inhibition of the growth of Haemophilus influenzae (MIC 0.15-1.50microg/mL) and good antibacterial properties towards Bacillus subtilis (MIC 3-25microg/mL). The minimal inhibitory concentration (MIC) was defined as the lowest concentration of compound inhibiting the growth of each strain. The antibacterial effectiveness was confirmed against a number of Gram positive bacteria, including methicillin-resistant Staphylococcus aureus. Yeasts and moulds showed a low susceptibility, except the dermatophyte mould Epidermophyton floccosum that is inhibited at concentrations ranging from 6 to 50microg/mL. In general, the antimicrobial activity of the thiophene derivatives was greater than that of the isonicotinic analogues.     

4-Alkyl and 4,4'-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives as new inhibitors of bacterial cell wall biosynthesis

Over 195 4-alkyl and 4,4-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives were synthesized, utilizing microwave accelerated synthesis, for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good activity against MurB in vitro and low MIC values against gram-positive bacteria, particularly penicillin-resistant Streptococcus pneumoniae (PRSP). Derivative 7l demonstrated antibacterial activity against both gram-positive and gram-negative bacteria. Derivatives 7f and 10a also demonstrated potent nanomolar Kd values in their binding to MurB.     

Synthesis and antibacterial activity of C2-fluoro, C6-carbamate ketolides, and their C9-oximes

Novel C6-carbamate ketolides with C2-fluorination and C9-oximation have been synthesized. The best compounds in this series displayed MIC values of 0.03-0.12 microg/mL against streptococci containing erm and mef resistance determinants and 2-4 microg/mL against Haemophilus influenzae. Several compounds also showed measurable activity against erm(B)-containing enterococci with MIC values of 2-8 microg/mL. In vivo activity was adversely affected by fluorination, possibly as a result of increased serum protein binding.     

Synthesis and antimicrobial activity of novel 2-thiazolylimino-5-arylidene-4-thiazolidinones

New 2-thiazolylimino-5-arylidene-4-thiazolidinones (compounds 4a-j), unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria, yeasts and mould. The compounds were very potent towards all tested Gram positive microorganisms (MIC ranging from 0.03 to 6 microg/mL in most of the cases) and Gram negative Haemophilus influenzae (MIC 0.15-1.5 microg/mL), whereas no effectiveness was exhibited against Gram negative Escherichia coli and fungi up to the concentration of 100 microg/mL. The 5-arylidene derivatives showed an antibacterial efficacy considerably greater than that of the parent 2-(thiazol-2-ylimino)thiazolidin-4-one 3, suggesting that the substituted and unsubstituted 5-arylidene moiety plays an important role in enhancing the antimicrobial properties of this class of compounds. The remarkable inhibition of the growth of penicillin-resistant staphylococci makes these substances promising agents also for the treatment of infections caused by microorganisms resistant to currently available drugs.     

Review of the in vitro activity and potential clinical efficacy of levofloxacin in the treatment of anaerobic infections

The activity of levofloxacin against aerobic bacteria has been well documented both in vitro and clinically, but its anaerobic activity has been infrequently studied. This new fluoroquinolone exhibits good in vitro activity (MIC(S) < or =2.0 microg/mL) against many anaerobic pathogens associated with acute sinusitis, bite wounds, and other soft-tissue infections. It is less active against Bacteroides fragilis (MIC (90)=2-4 microg/mL ) and has poor inhibitory activity against non-fragilis B. fragilis group species that are associated with gastrointestinal and genitourinary tract infections. Levofloxacin does not antagonize the in vitro activity of clindamycin and metronidazole and often provides additive or synergistic activity against anaerobic bacteria with these agents. In pharmacodynamic models, levofloxacin exhibits rapid bactericidal activity at 2-4 times the MIC of anaerobic bacteria. Prolonged killing is observed when the area-under-the concentration-time-curve to MIC ratio is greater than 40. In clinical efficacy trials, levofloxacin has been effective in the treatment of patients with gynecologic, skin and skin-structure, and bone infections involving anaerobic pathogens. Both micro-biologic and pharmacodynamic studies support further evaluations of levofloxacin in the treatment of selective mixed aerobic/anaerobic infections.     

Antimicrobial susceptibilities of Bacteroides fragilis and Bacteroides thetaiotaomicron strains isolated from clinical specimens and human intestinal microbiota

Species of Bacteroides fragilis group bacteria are the most prevalent pathogens and have the highest resistance rates to antimicrobial agents among anaerobic bacteria. Infections due to these micro-organisms often originate from patient's own intestinal microbiota. The objective of the study was to determine and compare the susceptibility profiles of clinical and intestinal B. fragilis and B. thetaiotaomicron strains against certain antimicrobials. Isolates were identified by conventional methods and API-20 A. Susceptibility tests were performed according to recommendations of NCCLS (M 11-A4) agar dilution methods. Beta-lactamase production was determined with nitrocefin discs. Forty-five clinical isolates (33 B. fragilis and 12 B. thetaiotaomicron) were from following sites: blood (n:8), intra-abdominal abscess (n:7), soft tissue (n:26), and miscellaneous foci of infection (n:4). Fifty B. fragilis and 60 B. thetaiotaomicron isolates from intestinal microbiota of individuals with no history of antimicrobial treatment within last 30 days were also examined. Beta-lactamase production was detected in 93% of clinical and 99% of intestinal isolates. The organisms including intestinal isolates were uniformly susceptible to metronidazole. The MIC90s of other antibiotics and resistance rates of all clinical isolates to those antibiotics were as follows: 256 microg/mL (93%) for ampicillin, 128 microg/mL (13%) for piperacillin, 64 microg/mL (11%) for cefoxitin, 1 microg/mL (2%) for amoxicillin-clavulanate, 0.5 microg/mL (2%) for imipenem, >256 microg/mL (36%) for clindamycin, 8 microg/mL (2%) for chloramphenicol. Intestinal isolates demonstrated similar resistance rates and MIC90s. Metronidazole, imipenem, amoxicillin-clavulanate seem to be effective drugs against these bacteria in Turkey.     

Carboxylic acid and phosphate ester derivatives of fluconazole: synthesis and antifungal activities

Two classes of fluconazole derivatives, (a) carboxylic acid esters and (b) fatty alcohol and carbohydrate phosphate esters, were synthesized and evaluated in vitro against Cryptococcus neoformans, Candida albicans, and Aspergillus niger. All carboxylic acid ester derivatives of fluconazole (1a-l), such as O-2-bromooctanoylfluconazole (1g, MIC=111 microg/mL) and O-11-bromoundecanoylfluconazole (1j, MIC=198 microg/mL), exhibited higher antifungal activity than fluconazole (MIC > or = 4444 microg/mL) against C. albicans ATCC 14053 in SDB medium. Several fatty alcohol phosphate triester derivatives of fluconazole, such as 2a, 2b, 2f, 2g, and 2h, exhibited enhanced antifungal activities against C. albicans and/or A. niger compared to fluconazole in SDB medium. For example, 2-cyanoethyl-omega-undecylenyl fluconazole phosphate (2b) with MIC value of 122 microg/mL had at least 36 times greater antifungal activity than fluconazole against C. albicans in SDB medium. Methyl-undecanyl fluconazole phosphate (2f) with a MIC value of 190 microg/mL was at least 3-fold more potent than fluconazole against A. niger ATCC 16404. All compounds had higher estimated lipophilicity and dermal permeability than those for fluconazole. These results demonstrate the potential of these antifungal agents for further development as sustained-release topical antifungal chemotherapeutic agents.     

Synthesis, biological activity, and SAR of antimycobacterial 2- and 8-substituted 6-(2-furyl)-9-(p-methoxybenzyl)purines

A number of 6-(2-furyl)-9-(p-methoxybenzyl)purines carrying a variety of substituents in the 2- or 8-position have been synthesized and their ability to inhibit growth of Mycobacterium tuberculosis in vitro has been determined. It is demonstrated that sterical hindrance in the purine 8-position reduces activity and that C-8 should be unsubstituted. In the purine 2-position small, hydrophobic substituents are beneficial. The electronic properties of the 2-substituents appear to have only a minor influence on bioactivity. The compounds studied exhibit low toxicity toward mammalian cells (VERO cells) and are essentially inactive toward Staphylococcus aureus and Escherichia coli. The most active and selective antimycobacterial in the series detected to date is the novel 2-methyl-6-furyl-9-(p-methoxybenzyl)purine with MIC=0.20 microg/mL against M. tuberculosis and IC(50) against VERO cells >62.5 microg/mL. Also the novel 2-fluoro analog and the previously known 2-chloro compound, both with MIC=0.39 microg/mL, are highly interesting drug candidates.     

A novel class of selective anti-Helicobacter pylori agents 2-oxo-2H-chromene-3-carboxamide derivatives

A novel class of selective anti-Helicobacter pylori agents, 2-oxo-2H-chromene-3-carboxamide derivatives, were prepared and evaluated for their anti-bacterial activity. All synthesized compounds showed little or no activity against different species of Gram-positive and Gram-negative bacteria and against various strains of pathogenic fungi. Some of them exhibited a potent and specific inhibitory effect on the growth of H. pylori, including metronidazole-resistant strains, in the 0.0039-16 microg/mL MIC range. A cytotoxic screening by the Trypan blue dye exclusion assay was also carried out on the most active compounds as anti-H. pylori agents. Among the derivatives examined for their cytotoxic potential, a number of them induced low cytotoxic effects.     

3-Phenyl-5-methyl-2H,5H-furan-2-ones: tuning antifungal activity by varying substituents on the phenyl ring

A series of racemic 3-phenyl-5-methyl-2H,5H-furan-2-ones related to a natural product, (-)incrustoporine, was synthesized, and their antifungal activity evaluated. The key structural feature, furanone ring, was closed via H2SO4-mediated cyclization of 2-phenylpent-4-enoic acids. The compounds displayed antifungal activity, especially against filamentous fungi. Expressed as the minimum inhibition concentration (MIC) in micromol/L, the activity of the most promising derivative against Absidia corymbifera matched that of ketoconazole (31.25 micromol/L). In terms of microg/mL, the substance was more active (7.6 microg/mL) than this standard antifungal drug (16.6 microg/mL).     

Physicochemical characterization and antimicrobial properties of rhamnolipids produced by Pseudomonas aeruginosa 47T2 NCBIM 40044

Pseudomonas aeruginosa 47T2, grown in submerged culture with waste frying oil as a carbon source, produced a mixture of rhamnolipids with surface activity. Up to 11 rhamnolipid homologs (Rha-Rha-C(8)-C(10); Rha-C(10)-C(8)/Rha-C(8)-C(10);Rha-Rha-C(8)-C(12:1); Rha-Rha-C(10)-C(10); Rha-Rha-C(10)-C(12:1); Rha-C(10)-C(10); Rha-Rha-C(10)-C(12)/Rha-Rha-C(12)-C(10); Rha-C(10)-C(12:1)/Rha-C(12:1)-C(10); Rha-Rha-C(12:1)-C(12); Rha-Rha-C(10)-C(14:1); Rha-C(10)-C(12)/Rha-C(12)-C(10)) were isolated from cultures of P. aeruginosa 47T2 from waste frying oil and identified by HPLC-MS analysis. This article deals with the production, isolation, and chemical characterization of the rhamnolipid mixture RL(47T2). The physicochemical and biological properties of RL(47T2) as a new product were also studied. Its surface tension decreased to 32.8 mN/m; and the interfacial tension against kerosene to 1 mN/m. The critical micellar concentration for RL(47T2) was 108.8 mg/mL. The product showed excellent antimicrobial properties. Antimicrobial activity was evaluated according to the minimum inhibitory concentration (MIC), the lowest concentration of an antimicrobial agent that inhibits development of visible microbial growth. Low MIC values were found for bacteria Serratia marcescens (4 microg/mL), Enterobacter aerogenes (8 microg/mL), Klebsiella pneumoniae (0.5 microg/mL), Staphylococcus aureus and Staphylococcus epidermidis (32 microg/mL), Bacillus subtilis (16 microg/mL), and phytopathogenic fungal species: Chaetonium globosum (64 microg/mL), Penicillium funiculosum (16 microg/mL), Gliocadium virens (32 microg/mL) and Fusarium solani (75 microg/mL).     

Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4-(adamantan-1-yl)-2-substituted quinolines

Structural optimization of the previously identified 4-(adamantan-1-yl)-2-quinolinecarbohydrazide (AQCH, MIC=6.25 microg/mL, 99% inhibition, Mycobacterium tuberculosis H37Rv) has led to two series of 4-(adamantan-1-yl)-2-substituted quinolines (Series 1-2). All new derivatives were evaluated in vitro for antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Several 4-adamantan-1-yl-quinoline-2-carboxylic acid N'-alkylhydrazides (Series 1) described herein showed promising inhibitory activity. In particular, analogs 7, 9, 20, and 21 displayed MIC of 3.125 microg/mL. Further investigation of AQCH by its reaction with various aliphatic, aromatic, and heteroaromatic aldehydes led to the synthesis of 4-adamantan-1-yl-quinoline-2-carboxylic acid alkylidene hydrazides (Series 2). Analogs 42-44 and 48 have produced promising antimycobacterial activities (99% inhibition) at 3.125 microg/mL against drug-sensitive M. tuberculosis H37Rv strain. The most potent analog 35 of the series produced 99% inhibition at 1.00 microg/mL against drug-sensitive strain, and MIC of 3.125 microg/mL against isoniazid-resistant TB strain. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by three methods-comparative molecular field analysis (CoMFA), CoMFA with inclusion of a hydropathy field (HINT), and comparative molecular similarity indices analysis (CoMSIA). Several statistically significant CoMFA, CoMFA with HINT, and CoMSIA models were generated. Prediction of the activity of a test set of molecules was the best for the CoMFA model generated with database alignment. Based on the CoMFA contours, we have tried to explain the structure-activity relationships of the compounds reported herein.     

Synthesis, absolute stereochemistry and molecular design of the new antifungal and antibacterial antibiotic produced by Streptomyces sp.201

The absolute stereochemistry of the new antifungal and antibacterial antibiotic produced by Streptomyces sp.201 has been established by achieving the total synthesis of the product. A series of analogues have also been synthesized by changing the side chain and their bioactivity assessed against different microbial strains. Among them, 1e (R = C8H17) was found to be the most potent with MIC of 8 microg/mL against Mycobacterium tuberculosis, 12 microg/mL against Escherichia coli and 16 microg/mL against Bacillus subtilis 6 microg/mL against Proteus vulgaris. This was followed by 1b (R = C5H11) with MIC of 10-20 microg/mL range and 1d (R = C7H15) with MIC of 14-24 g/mL, whereas 1a (R = C4H9) and 1f (R = C18H35) were found to be completely inactive. Besides, 1c (R = C6H13) showed certain extent of antibacterial activity in the range of 24-50 microg/mL. Mycobacterium tuberculosis was very sensitive to 1e (R = C8H17) with MIC of 8 microg/mL. Antifungal activity of analogues 1d (R = C7H15) and 1e, (R = C8H17) against Fusarium oxysporum and Rhizoctonia solani were found promising with MFCs in the 15-18 microg/mL range.     

Conformationally restricted analogs of deoxynegamycin

Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC(50)=8.2 microM; 44, IC(50)=6.6 microM; 35e(2), IC(50)=1 microM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC=4-16 microg/mL; Klebsiella pneumoniae, MIC=8 microg/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED(50)=4.8 mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules.     

Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus

Vancomycin is mainly used as an antibacterial agent of last resort, but recently vancomycin-resistant bacterial strains have been emerging. Although new antimicrobials have been developed in order to overcome drug-resistant bacteria, many are structurally complex beta-lactams or quinolones. In this study, we aimed to create new anti-drug-resistance antibacterials which can be synthesized in a few steps from inexpensive starting materials. Since sulfa drugs function as p-aminobenzoic acid mimics and inhibit dihydropteroate synthase (DHPS) in the folate pathway, we hypothesized that sulfa derivatives would act as folate metabolite-mimics and inhibit bacterial folate metabolism. Screening of our sulfonanilide libraries, including benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors, led us to discover benzenesulfonanilides with potent anti-methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant Enterococcus (VRE) activity, that is, N-3,5-bis(trifluoromethyl)phenyl-3,5-dichlorobenzenesulfonanilide (16b) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)], and 3,5-bis(trifluoromethyl)-N-(3,5-dichlorophenyl)benzenesulfonanilide (16c) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)]. These compounds are more active than vancomycin [MIC=2.0microg/mL (MRSA), 125microg/mL (VRE)], but do not possess an amino group, which is essential for DHPS inhibition by sulfa drugs. These results suggested that the mechanism of antibacterial action of compounds 16b and 16c is different from that of sulfa drugs. We also confirmed the activity of these compounds against clinical isolates of Gram-positive bacteria.     

Antibacterial activity of triterpene acids and semi-synthetic derivatives against oral pathogens

Triterpene acids (ursolic, oleanoic, gypsogenic, and sumaresinolic acids) isolated from Miconia species, along with a mixture of ursolic and oleanolic acids and a mixture of maslinic and 2-a-hydroxyursolic acids, as well as ursolic acid derivatives were evaluated against the following microorganisms: Streptococcus mutans, Streptococcus mitis, Streptococcus sanguinis, Streptococcus salivarius, Streptococcus sobrinus, and Enterococcus faecalis, which are potentially responsible for the formation of dental caries in humans. The microdilution method was used for the determination of the minimum inhibitory concentration (MIC) during the evaluation of the antibacterial activity. All the isolated compounds, mixtures, and semi-synthetic derivatives displayed activity against all the tested bacteria, showing that they are promising antiplaque and anticaries agents. Ursolic and oleanolic acids displayed the most intense antibacterial effect, with MIC values ranging from 30 microg/mL to 80 microg/mL. The MIC values of ursolic acid derivatives, as well as those obtained for the mixture of ursolic and oleanolic acids showed that these compounds do not have higher antibacterial activity when compared with the activity observed with either ursolic acid or oleanolic acid alone. With regard to the structure-activity relationship of triterpene acids and derivatives, it is suggested that both hydroxy and carboxy groups present in the triterpenes are important for their antibacterial activity against oral pathogens.     

Novel and potent oxazolidinone antibacterials featuring 3-indolylglyoxamide substituents

Novel oxazolidinone antibacterials bearing a variety of 3-indolylglyoxamide substituents have been explored in an effort to improve the spectrum and potency of this class of agents. A subclass of this series was also made with the diversity at C-5 terminus. These derivatives have been screened against a panel of clinically relevant Gram-positive pathogens and fastidious Gram-negative organisms. Several analogs in this series were identified with in vitro activity superior to linezolid (MIC=0.25-2 microg/mL). Compounds 10a, 10c, 10e and 10f displayed activity against linezolid resistant Gram-positive organisms (MIC=2-4 microg/mL). Selected oxazolidinones were evaluated for in vivo efficacy against a mouse systemic infection model.