scholarly journals Laccase-Catalyzed Derivatization of Antibiotics with Sulfonamide or Sulfone Structures

2021 ◽  
Vol 9 (11) ◽  
pp. 2199
Author(s):  
Annett Mikolasch ◽  
Veronika Hahn
Keyword(s):  
Oxidative Coupling ◽  
Multidrug Resistant ◽  
Amino Group ◽  
Hybrid Products ◽  
Primary Amino ◽  
Resistant Strains

Trametes spec. laccase (EC 1.10.3.2.) mediates the oxidative coupling of antibiotics with sulfonamide or sulfone structures with 2,5-dihydroxybenzene derivatives to form new heterodimers and heterotrimers. These heteromolecular hybrid products are formed by nuclear amination of the p-hydroquinones with the primary amino group of the sulfonamide or sulfone antibiotics, and they inhibited in vitro the growth of Staphylococcus species, including multidrug-resistant strains.

scholarly journals Laccase-catalyzed derivatization of 6-aminopenicillanic, 7-aminocephalosporanic and 7-aminodesacetoxycephalosporanic acid

AMB Express ◽  
2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Annett Mikolasch ◽  
Elke Hammer ◽  
Sabine Witt ◽  
Ulrike Lindequist
Keyword(s):  
Oxidative Coupling ◽  
Multidrug Resistant ◽  
Primary Amines ◽  
Dihydroxybenzoic Acid ◽  
Resistant Strains

Abstract Trametes spec. laccase (EC 1.10.3.2.) mediates the oxidative coupling of 6-aminopenicillanic, 7-aminocephalosporanic, and 7-aminodesacetoxycephalosporanic acid with 2,5-dihydroxybenzoic acid derivatives to form new penicillin and cephalosporin structures, respectively. The heteromolecular hybrid dimers are formed by nuclear amination of the p-hydroquinones with the primary amines and inhibited in vitro the growth of Staphylococcus species, including some multidrug-resistant strains.

scholarly journals 1280. In-Vitro Activity of Cefiderocol, Imipenem/Relebactam, & Ceftazidime/Avibactam in Ceftolozane/Tazobactam Resistant Strains of Multidrug Resistant Pseudomonas aeruginosa

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S655-S655
Author(s):  
Daniel Navas ◽  
Angela Charles ◽  
Amy Carr ◽  
Jose Alexander
Keyword(s):  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
Resistance Testing ◽  
Clinical Samples ◽  
In Vitro Activity ◽  
Carbapenemase Gene ◽  
Resistant Strains

Abstract Background The activity of imipenem/relebactam (I/R), ceftazidime/avibactam (CZA) and cefiderocol (FDC) were evaluated against clinical isolates of multidrug resistant (MDR) strains of P. aeruginosa which was resistant to ceftolozane/tazobactam (C/T). The recent increase of MDR P. aeruginosa strains isolated from clinical samples has prompted research and development of new antimicrobials that can withstand its multiple resistance mechanisms. C/T is an effective option for treatment of MDR P. aeruginosa in our facility with only 10% of resistance in MDR strains, but the emergence of resistance may occur due to the presence of a carbapenemase gene or an ampC mutation. Methods Antimicrobial susceptibility testing for C/T Etest® (bioMérieux, Inc.) were performed on all MDR strains initially screened by the VITEK2® (bioMérieux, Inc.). 10% (n=20) of all MDR isolates were resistant to C/T by the CLSI 2019 breakpoints. These resistant isolates were tested for presence of a carbapenemase gene using the GeneXpert CARBA-R (Cepheid®) PCR and against CZA Etest® (bioMérieux, Inc.) I/R gradient strips (Liofilchem®) and FDC broth microdilution (Thermo Scientific™ Sensititre™). Results A total of 20 clinical isolates of MDR P. aeruginosa resistant to C/T were tested following standardized CLSI protocols and techniques. All 20 isolates were screened for the presence of a carbapenemase gene (blaVIM, blaNDM, blaKPC, blaOXA-48, blaIMP). A blaVIM gene was detected in 6 (30%) out of 20 isolates. FDC demonstrated the greatest activity with 85% (n=17) of susceptible isolates (CLSI MIC <4µg/dL). CZA (CLSI MIC <8µg/dL) and I/R (FDA MIC <2µg/dL) showed 15% (n=3) and 10% (n=2) of susceptible isolates respectively. FDC was active against all 6 blaVIM isolates, where all 6 strains were resistant to CZA and I/R as expected. 3 isolates tested non-susceptible against FDC; additional characterization was not performed at this time. Conclusion Based on these results, FDC demonstrated the greatest in-vitro activity against C/T resistant strains of MDR P. aeruginosa. FDC also demonstrated activity against all 6 MDR P. aeruginosa carrying blaVIM gene. FDC is a strong option to consider on MDR P. aeruginosa strains based on a resistance testing algorithm and a cost/effective protocol. Disclosures All Authors: No reported disclosures

scholarly journals Silver Nanoparticles and Their Antibacterial Applications

2021 ◽  
Vol 22 (13) ◽  
pp. 7202
Author(s):  
Tamara Bruna ◽  
Francisca Maldonado-Bravo ◽  
Paul Jara ◽  
Nelson Caro
Keyword(s):  
Silver Nanoparticles ◽  
Antibacterial Agents ◽  
Multidrug Resistant ◽  
Secondary Effects ◽  
Cytotoxic Effects ◽  
Factors Affecting ◽  
Gram Positive Bacteria ◽  
Resistant Strains

Silver nanoparticles (AgNPs) have been imposed as an excellent antimicrobial agent being able to combat bacteria in vitro and in vivo causing infections. The antibacterial capacity of AgNPs covers Gram-negative and Gram-positive bacteria, including multidrug resistant strains. AgNPs exhibit multiple and simultaneous mechanisms of action and in combination with antibacterial agents as organic compounds or antibiotics it has shown synergistic effect against pathogens bacteria such as Escherichia coli and Staphylococcus aureus. The characteristics of silver nanoparticles make them suitable for their application in medical and healthcare products where they may treat infections or prevent them efficiently. With the urgent need for new efficient antibacterial agents, this review aims to establish factors affecting antibacterial and cytotoxic effects of silver nanoparticles, as well as to expose the advantages of using AgNPs as new antibacterial agents in combination with antibiotic, which will reduce the dosage needed and prevent secondary effects associated to both.

scholarly journals In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

2010 ◽  
Vol 54 (6) ◽  
pp. 2291-2302 ◽  
Author(s):  
Malcolm G. P. Page ◽  
Clothilde Dantier ◽  
Eric Desarbre
Keyword(s):  
Multidrug Resistant ◽  
Unusual Property ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
High Affinity ◽  
Class A ◽  
Carbapenem Resistant ◽  
Lactam Antibiotic ◽  
Resistant Strains

ABSTRACT BAL30072 is a new monocyclic β-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with β-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC90s were 4 μg/ml for MDR Acinetobacter spp. and 8 μg/ml for MDR P. aeruginosa, whereas the MIC90 of meropenem for the same sets of isolates was >32 μg/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-β-lactamases that conferred resistance to all other β-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-β-lactamase. Unlike other monocyclic β-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.

scholarly journals Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Priyanka Panwar ◽  
Kepa K. Burusco ◽  
Muna Abubaker ◽  
Holly Matthews ◽  
Andrey Gutnov ◽  
...  
Keyword(s):  
De Novo ◽  
Antimalarial Activity ◽  
Drug Repositioning ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Synthetic Analogue ◽  
80S Ribosome ◽  
Content Type ◽  
Resistant Strains

ABSTRACT Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (−)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than did (−)-S,S-dehydroisoemetine. (−)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (−)-S,S-dehydroisoemetine (IC50, 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (−)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (−)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.

scholarly journals In Vitro and In Vivo Anti-Salmonella Evaluation of Pectin Extracts and Hydrolysates from “Cas Mango” (Spondias dulcis)

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Denis Zofou ◽  
Golda Lum Shu ◽  
Josepha Foba-Tendo ◽  
Merveille Octavie Tabouguia ◽  
Jules-Clement N. Assob
Keyword(s):  
Multidrug Resistant ◽  
Positive Control ◽  
Resistant Bacteria ◽  
Therapeutic Effects ◽  
Diffusion Technique ◽  
Resistant Strains ◽  
Almost All ◽  
Broth Dilution

Background. The threat to human health posed by multidrug-resistant strains of Salmonella typhi (S. typhi) and Salmonella paratyphi (S. paratyphi) is of growing concern. Generally, there has been increasing resistance and even multidrug resistance to almost all classes of antibiotics. This has rendered treatment with antibiotics difficult and costly. The present study investigated the bioactivity of pectin and pectin hydrolysates derived from a local fruit, Spondias dulcis, against four strains of Salmonellae. Methods. Pectin was extracted from alcohol extractives-free peel by acidic hydrolysis at a temperature of 80°C for one hour at pH 2 and 4. The pectin was precipitated with 95% alcohol at an extract to alcohol ratio of 1:10 v/v. Antimicrobial activity was determined using agar well diffusion technique. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined using the broth dilution technique. An in vivo study was then carried out with the bioactive extracts against the most resistant bacteria strain, to fully establish the therapeutic effect of these extracts. Balb/C mice were used, and ciprofloxacin was the positive control antibiotic. The extracts were administered to mice at two doses, 5mg/Kg and 10mg/Kg. The efficacy of extracts in the treatment of typhoid was evaluated based on survival rate, change in body weight, and change in bacteria load. Results. Only one of the extracts (crude pectin pH 2.5) was active against all the Salmonellae by well diffusion, and the growth inhibition varied from 12mm to 15mm at100 μg/ml. Three of the extracts (crude pectin pH 2.5, pH 4, 12h hydrolysate, and pH 4, 1h hydrolysate) had MIC and MBC against all four Salmonellae strains with MIC ranging from 5.68 to 44.45 μg/ml and MBC from 11.36 to 44.45 μg/mL. Three treatments, namely, the pH4-12 hr, hydrolysate at 10mg/Kg and 5mg/Kg, and the pH4-1hr, hydrolysate at 10mg/Kg, had therapeutic effects against Salmonella infection in mice. Conclusion. The present study highlights the potential of pectin oligosaccharides as new source of anti-Salmonella drugs. Further investigations including exploration of mechanism of action of the most active pectin extracts/hydrolysates are envisaged.

scholarly journals In Vitro Activities of RWJ-54428 (MC-02,479) against Multiresistant Gram-Positive Bacteria

2001 ◽  
Vol 45 (5) ◽  
pp. 1422-1430 ◽  
Author(s):  
Suzanne Chamberland ◽  
Johanne Blais ◽  
Monica Hoang ◽  
Cynthia Dinh ◽  
Dylan Cotter ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Penicillin G ◽  
Significant Activity ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Level Of Activity ◽  
Resistant Strains ◽  
High Level

ABSTRACT RWJ-54428 (MC-02,479) is a new cephalosporin with a high level of activity against gram-positive bacteria. In a broth microdilution susceptibility test against methicillin-resistant Staphylococcus aureus (MRSA), RWJ-54428 was as active as vancomycin, with an MIC at which 90% of isolates are inhibited (MIC90) of 2 μg/ml. For coagulase-negative staphylococci, RWJ-54428 was 32 times more active than imipenem, with an MIC90 of 2 μg/ml. RWJ-54428 was active against S. aureus, Staphylococcus epidermidis, and Staphylococcus haemolyticus isolates with reduced susceptibility to glycopeptides (RWJ-54428 MIC range, ≤0.0625 to 1 μg/ml). RWJ-54428 was eight times more potent than methicillin and cefotaxime against methicillin-susceptible S. aureus (MIC90, 0.5 μg/ml). For ampicillin-susceptible Enterococcus faecalis (including vancomycin-resistant and high-level aminoglycoside-resistant strains), RWJ-54428 had an MIC90 of 0.125 μg/ml. RWJ-54428 was also active against Enterococcus faecium, including vancomycin-, gentamicin-, and ciprofloxacin-resistant strains. The potency against enterococci correlated with ampicillin susceptibility; RWJ-54428 MICs ranged between ≤0.0625 and 1 μg/ml for ampicillin-susceptible strains and 0.125 and 8 μg/ml for ampicillin-resistant strains. RWJ-54428 was more active than penicillin G and cefotaxime against penicillin-resistant, -intermediate, and -susceptible strains ofStreptococcus pneumoniae (MIC90s, 0.25, 0.125, and ≤0.0625 μg/ml, respectively). RWJ-54428 was only marginally active against most gram-negative bacteria; however, significant activity was observed against Haemophilus influenzae andMoraxella catarrhalis (MIC90s, 0.25 and 0.5 μg/ml, respectively). This survey of the susceptibilities of more than 1,000 multidrug-resistant gram-positive isolates to RWJ-54428 indicates that this new cephalosporin has the potential to be useful in the treatment of infections due to gram-positive bacteria, including strains resistant to currently available antimicrobials.

scholarly journals In Vitro Activity and MIC of Sitafloxacin against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis Isolated in Thailand

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Manoon Leechawengwongs ◽  
Therdsak Prammananan ◽  
Sarinya Jaitrong ◽  
Pamaree Billamas ◽  
Nampueng Makhao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Concentration ◽  
Multidrug Resistant ◽  
Quinolone Resistance ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT New fluoroquinolones (FQs) have been shown to be more active against drug-resistant Mycobacterium tuberculosis strains than early FQs, such as ofloxacin. Sitafloxacin (STFX) is a new fluoroquinolone with in vitro activity against a broad range of bacteria, including M. tuberculosis. This study aimed to determine the in vitro activity of STFX against all groups of drug-resistant strains, including multidrug-resistant M. tuberculosis (MDR M. tuberculosis), MDR M. tuberculosis with quinolone resistance (pre-XDR), and extensively drug-resistant (XDR) strains. A total of 374 drug-resistant M. tuberculosis strains were tested for drug susceptibility by the conventional proportion method, and 95 strains were randomly submitted for MIC determination using the microplate alamarBlue assay (MABA). The results revealed that all the drug-resistant strains were susceptible to STFX at a critical concentration of 2 μg/ml. Determination of the MIC90s of the strains showed different MIC levels; MDR M. tuberculosis strains had a MIC90 of 0.0625 μg/ml, whereas pre-XDR and XDR M. tuberculosis strains had identical MIC90s of 0.5 μg/ml. Common mutations within the quinolone resistance-determining region (QRDR) of gyrA and/or gyrB did not confer resistance to STFX, except that double mutations of GyrA at Ala90Val and Asp94Ala were found in strains with a MIC of 1.0 μg/ml. The results indicated that STFX had potent in vitro activity against all the groups of drug-resistant M. tuberculosis strains and should be considered a new repurposed drug for treatment of multidrug-resistant and extensively drug-resistant TB.

scholarly journals Clinically Relevant Plasma Concentrations of Colistin in Combination with Imipenem Enhance Pharmacodynamic Activity against Multidrug-Resistant Pseudomonas aeruginosa at Multiple Inocula

2011 ◽  
Vol 55 (11) ◽  
pp. 5134-5142 ◽  
Author(s):  
Phillip J. Bergen ◽  
Alan Forrest ◽  
Jürgen B. Bulitta ◽  
Brian T. Tsuji ◽  
Hanna E. Sidjabat ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Therapy ◽  
Systematic Study ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Bacterial Killing ◽  
Content Type ◽  
Resistant Strains ◽  
Time Kill

ABSTRACTThe use of combination antibiotic therapy may be beneficial against rapidly emerging resistance inPseudomonas aeruginosa. The aim of this study was to systematically investigatein vitrobacterial killing and resistance emergence with colistin alone and in combination with imipenem against multidrug-resistant (MDR)P. aeruginosa. Time-kill studies were conducted over 48 h using 5 clinical isolates and ATCC 27853 at two inocula (∼106and ∼108CFU/ml); MDR, non-MDR, and colistin-heteroresistant and -resistant strains were included. Nine colistin-imipenem combinations were investigated. Microbiological response was examined by log changes at 6, 24, and 48 h. Colistin combined with imipenem at clinically relevant concentrations increased the levels of killing of MDR and colistin-heteroresistant isolates at both inocula. Substantial improvements in activity with combinations were observed across 48 h with all colistin concentrations at the low inoculum and with colistin at 4× and 16× MIC (or 4 and 32 mg/liter) at the high inoculum. Combinations were additive or synergistic against imipenem-resistant isolates (MICs, 16 and 32 mg/liter) at the 106-CFU inoculum in 9, 11, and 12 of 18 cases (i.e., 9 combinations across 2 isolates) at 6, 24, and 48 h, respectively, and against the same isolates at the 108-CFU inoculum in 11, 7, and 8 cases, respectively. Against a colistin-resistant strain (MIC, 128 mg/liter), combinations were additive or synergistic in 9 and 8 of 9 cases at 24 h at the 106- and 108-CFU inocula, respectively, and in 5 and 7 cases at 48 h. This systematic study provides important information for optimization of colistin-imipenem combinations targeting both colistin-susceptible and colistin-resistant subpopulations.

scholarly journals Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

2012 ◽  
Vol 56 (7) ◽  
pp. 3475-3480 ◽  
Author(s):  
Sovitj Pou ◽  
Rolf W. Winter ◽  
Aaron Nilsen ◽  
Jane Xu Kelly ◽  
Yuexin Li ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Plasmodium Yoelii ◽  
Significant Activity ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Derivatives Of

ABSTRACTSontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains ofPlasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC50s) against drug-sensitive and multidrug-resistant strains andin vivoefficacy against patent infections ofPlasmodium yoeliiin mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.

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