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1.
Sci Rep ; 14(1): 2749, 2024 02 02.
Article in English | MEDLINE | ID: mdl-38302510

ABSTRACT

The emergence and dissemination of carbapenem-resistant species of Acinetobacter and Pseudomonas have become a serious health concern. Routine antimicrobial disk susceptibility tests in clinical laboratories cannot distinguish between isolates that are highly carbapenem-resistant and those that are moderately carbapenem-resistant. The present study describes antimicrobial susceptibility tests using disks containing high doses (1000 µg) of meropenem. The diameters of inhibition zones were significantly negatively correlated with the MICs of Pseudomonas and Acinetobacter species for meropenem (R2: 0.93 and 0.91, respectively) and imipenem (R2: 0.75 and 0.84, respectively). Double disk synergy tests using clavulanic acid or sodium mercaptoacetate can detect ESBL or MBL producers. Susceptibility tests using disks containing high doses of meropenem can easily detect highly carbapenem-resistant isolates in a quantitative manner. These disks may be useful in bacteriological laboratories because of their technical ease, stability, and relatively low cost.


Subject(s)
Acinetobacter , Anti-Infective Agents , Meropenem/pharmacology , Pseudomonas , Thienamycins/pharmacology , Carbapenems/pharmacology , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , beta-Lactamases
2.
Clin Infect Dis ; 78(6): 1482-1489, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38306577

ABSTRACT

BACKGROUND: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. METHODS: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. RESULTS: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04). CONCLUSIONS: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.


Subject(s)
Anti-Bacterial Agents , Klebsiella Infections , Klebsiella pneumoniae , Meropenem , Piperacillin, Tazobactam Drug Combination , Piperacillin , Humans , Meropenem/therapeutic use , Meropenem/pharmacology , Piperacillin, Tazobactam Drug Combination/therapeutic use , Piperacillin, Tazobactam Drug Combination/pharmacology , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Klebsiella pneumoniae/drug effects , Piperacillin/therapeutic use , Piperacillin/pharmacology , Klebsiella Infections/drug therapy , Klebsiella Infections/mortality , Bacteremia/drug therapy , Bacteremia/microbiology , Bacteremia/mortality , Escherichia coli/drug effects , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Escherichia coli Infections/mortality , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/therapeutic use , Penicillanic Acid/pharmacology , Ceftriaxone/therapeutic use , Ceftriaxone/pharmacology , Male , Female , Middle Aged , Thienamycins/therapeutic use , Thienamycins/pharmacology , Aged , Treatment Outcome
3.
Nanomedicine (Lond) ; 18(24): 1719-1731, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37965902

ABSTRACT

Aim: This study aimed to investigate the in vitro antimicrobial effect of gold nanoparticles capped with meropenem and imipenem against various strains and to evaluate the cytotoxic effect of gold nanoparticles on healthy human colon epithelial cells. Materials & methods: Gold nanoparticles were synthesized via the Turkevich method and tested for antimicrobial effects using broth microdilution. Cell culture studies were performed using a cytotoxicity assay with alamarBlue™. Results & conclusion: Nanoparticles (10-20 nm) with antibiotic coating were more effective against Escherichia coli, Proteus spp. and Serratia marcescens than pure antibiotics. They had a cytotoxic effect on cells at high concentrations but were safe at low concentrations.


Subject(s)
Anti-Infective Agents , Metal Nanoparticles , Humans , Meropenem/pharmacology , Imipenem/pharmacology , Gold , Thienamycins/pharmacology , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology
4.
J Med Microbiol ; 70(10)2021 Oct.
Article in English | MEDLINE | ID: mdl-34605760

ABSTRACT

The options available for treating infections with carbapenemase-producing Enterobacteriaceae (CPE) are limited; with the increasing threat of these infections, new treatments are urgently needed. Biapenem (BIPM) is a carbapenem, and limited data confirming its in vitro killing effect against CPE are available. In this study, we examined the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of BIPM for 14 IMP-1-producing Enterobacteriaceae strains isolated from the Okayama region in Japan. The MICs against almost all the isolates were lower than 0.5 µg ml-1, indicating susceptibility to BIPM, while approximately half of the isolates were confirmed to be bacteriostatic to BIPM. However, initial killing to a 99.9 % reduction was observed in seven out of eight strains in a time-kill assay. Despite the small data set, we concluded that the in vitro efficacy of BIPM suggests that the drug could be a new therapeutic option against infection with IMP-producing CPE.


Subject(s)
Anti-Bacterial Agents/pharmacology , Enterobacteriaceae/drug effects , Thienamycins/pharmacology , beta-Lactamases/metabolism , Drug Resistance, Bacterial , Enterobacteriaceae/enzymology , Microbial Sensitivity Tests
5.
Sci Rep ; 11(1): 10062, 2021 05 12.
Article in English | MEDLINE | ID: mdl-33980996

ABSTRACT

Thienamycin, the first representative of carbapenem antibiotics was discovered in the mid-1970s from soil microorganism, Streptomyces cattleya, during the race to discover inhibitors of bacterial peptidoglycan synthesis. Chemically modified into imipenem (N-formimidoyl thienamycin), now one of the most clinically important antibiotics, thienamycin is encoded by a thienamycin gene cluster composed of 22 genes (thnA to thnV) from S. cattleya NRRL 8057 genome. Interestingly, the role of all thn-genes has been experimentally demonstrated in the thienamycin biosynthesis, except thnS, despite its annotation as putative ß-lactamase. Here, we expressed thnS gene and investigated its activities against various substrates. Our analyses revealed that ThnS belonged to the superfamily of metallo-ß-lactamase fold proteins. Compared to known ß-lactamases such as OXA-48 and NDM-1, ThnS exhibited a lower affinity and less efficiency toward penicillin G and cefotaxime, while imipenem is more actively hydrolysed. Moreover, like most MBL fold enzymes, additional enzymatic activities of ThnS were detected such as hydrolysis of ascorbic acid, single strand DNA, and ribosomal RNA. ThnS appears as a MBL enzyme with multiple activities including a specialised ß-lactamase activity toward imipenem. Thus, like toxin/antitoxin systems, the role of thnS gene within the thienamycin gene cluster appears as an antidote against the produced thienamycin.


Subject(s)
Anti-Bacterial Agents/pharmacology , Cefotaxime/pharmacology , Cephamycins/pharmacology , Penicillin G/pharmacology , Streptomyces/drug effects , Thienamycins/pharmacology , beta-Lactamases/metabolism , Streptomyces/enzymology
6.
Pharmacol Rep ; 73(3): 786-795, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33515401

ABSTRACT

BACKGROUND: As a late mediator of sepsis, the role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies for sepsis. For repositioning of previously FDA-approved drugs to develop new therapies for human diseases, screening of chemical compound libraries, biological active, is an efficient method. Our study illustrates an example of drug repositioning of Biapenem (BIPM), a carbapenem antibiotic, for the modulation of HMGB1-induced septic responses. METHODS: We tested our hypothesis that BIPM inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model, antiseptic activity of BIPM was investigated from suppression of vascular permeability, pro-inflammatory proteins, and markers for tissue injury. RESULTS: BIPM significantly suppressed release of HMGB1 both in LPS-activated HUVECs (upto 60%) and the CLP-induced sepsis mouse model (upto 54%). BIPM inhibited hyperpermeability (upto 59%) and reduced HMGB1-mediated vascular disruptions (upto 62%), mortality (upto 50%), and also tissue injury including lung, liver, and kidney in mice. CONCLUSION: Reduction of HMGB1 release and septic mortality by BIPM (in vitro, from 5 to 15 µM for 6 h; in vivo, from 0.37 to 1.1 mg/kg, 24 h) indicate a possibility of successful repositioning of BIPM for the treatment of sepsis.


Subject(s)
HMGB1 Protein/metabolism , Sepsis/drug therapy , Signal Transduction/drug effects , Thienamycins/pharmacology , Animals , Cell Movement/drug effects , Cells, Cultured , Disease Models, Animal , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , Sepsis/metabolism , Sepsis/mortality
7.
J Med Microbiol ; 69(7): 928-931, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32584214

ABSTRACT

Introduction. The therapeutic options to treat Acinetobacter baumannii infections are very limited.Aim. Our aim was to evaluate the activity of sulbactam combined directly with avibactam or the ampicillin-sulbactam/ceftazidime-avibactam combination against extensively drug-resistant A. baumannii isolates.Methodology. Extensively drug-resistant A. baumannii isolates (n=127) collected at several South American hospitals were studied. Synergy with the sulbactam/avibactam combination was assessed in all isolates using the agar dilution method. Avibactam was used at a fixed concentration of 4 mg l-1. A disc diffusion synergy test was also performed. Synergy by a time-kill experiment was performed in a selected isolate.Results. Synergy with sulbactam/avibactam was demonstrated in 124 isolates and it showed MIC values ≤4 mg l-1. This synergy was not detected in the three New Delhi metallo-ß-lactamase-harbouring isolates. Similar results were observed with the disc diffusion synergy test of ampicillin-sulbactam/ceftazidime-avibactam. In the time-kill experiments, sulbactam/avibactam showed a rapid synergistic and bactericidal activity in ampicillin-sulbactam-resistant isolates.Conclusions. This study demonstrated that the sulbactam/avibactam combination displayed synergistic activity against A. baumannii isolates. This synergy was observed when both inhibitors were also used as part of the commercially available combinations: ampicillin-sulbactam and ceftazidime-avibactam.


Subject(s)
Acinetobacter Infections/therapy , Azabicyclo Compounds/metabolism , Sulbactam/pharmacology , Acinetobacter Infections/metabolism , Acinetobacter baumannii/metabolism , Ampicillin/pharmacology , Anti-Bacterial Agents/pharmacology , Azabicyclo Compounds/pharmacology , Ceftazidime/pharmacology , Drug Combinations , Drug Resistance, Bacterial/drug effects , Drug Resistance, Multiple, Bacterial/drug effects , Drug Therapy, Combination/methods , Humans , Microbial Sensitivity Tests , Thienamycins/pharmacology
8.
J Infect Chemother ; 26(7): 745-748, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32171658

ABSTRACT

Although the pneumococcal conjugate vaccine (PCV) has decreased the incidence of invasive pneumococcal disease (IPD) in children, cases of IPD caused by non-PCV serotypes have been increasing. Here, we report two cases of bacterial meningitis caused by meropenem-resistant Streptococcus pneumoniae; in both the cases, 13-valent PCV (PCV13) had been administered. The isolated S. pneumoniae strains were non-PCV13 serotype 35B and resistant to penicillin G, cefotaxime, and meropenem. In addition, multilocus sequence typing (MLST) revealed the sequence type (ST) to be 558. In case 1, a 6-month-old girl recovered without sequelae after antibiotic therapy comprising cefotaxime and vancomycin, whereas in case 2, a 9-month-old boy was treated with an empirical treatment comprising ceftriaxone and vancomycin administration. However, maintaining the blood concentration of vancomycin within the effective range was difficult, due to which the antibiotics were changed to panipenem/betamipron. During the treatment, he presented with seizures, which were effectively controlled with antiepileptic drugs. The rate of incidence of penicillin-susceptible IPD has been substantially increasing after the introduction of PCV. However, an upsurge in IPD cases due to multidrug-resistant (MDR) serotype 35B has been reported in countries where PCV13 was introduced before introducing in Japan. Moreover, an increase in the proportion of MDR serotype 35B and decrease in the susceptibility to broad-spectrum antimicrobials, including meropenem, have been reported. Hence, the number of meningitis cases caused by MDR serotype 35B/ST558 may increase in the future.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , Meningitis, Pneumococcal/drug therapy , Meropenem/pharmacology , Streptococcus pneumoniae/genetics , Anti-Bacterial Agents/therapeutic use , Cefotaxime/pharmacology , Cefotaxime/therapeutic use , Female , Humans , Infant , Male , Meningitis, Pneumococcal/blood , Meningitis, Pneumococcal/diagnosis , Meningitis, Pneumococcal/microbiology , Meropenem/therapeutic use , Microbial Sensitivity Tests , Multilocus Sequence Typing , Pneumococcal Vaccines/administration & dosage , Serotyping , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/isolation & purification , Thienamycins/pharmacology , Thienamycins/therapeutic use , Treatment Outcome , beta-Alanine/analogs & derivatives , beta-Alanine/pharmacology , beta-Alanine/therapeutic use
9.
Int J Mol Sci ; 21(4)2020 Feb 21.
Article in English | MEDLINE | ID: mdl-32098061

ABSTRACT

The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 µm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM2.5. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM2.5-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Enhanced myeloperoxidase (MPO) activity by PM2.5 in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM2.5 in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM2.5-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM2.5 increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM2.5-induced pulmonary injury.


Subject(s)
Drug Repositioning , Lung Injury , Lung , Particulate Matter/toxicity , Thienamycins/pharmacology , Animals , Beclin-1/immunology , Bronchoalveolar Lavage , Cytokines/immunology , Lung/immunology , Lung/pathology , Lung Injury/chemically induced , Lung Injury/drug therapy , Lung Injury/immunology , Lung Injury/pathology , Lymphocytes/immunology , Male , Mice , Mice, Inbred BALB C , Microtubule-Associated Proteins/immunology , Myeloid Differentiation Factor 88/immunology , TOR Serine-Threonine Kinases/immunology , Toll-Like Receptor 4/immunology
10.
Lett Appl Microbiol ; 70(3): 189-195, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31808159

ABSTRACT

The aim of this study was to investigate the in vitro interactions of ambroxol hydrochloride (ABH) or amlodipine (AML) with commonly used antibacterial agents, including meropenem, imipenem-cilastatin sodium, biapenem, cefoperazone-sulbactam, polymyxin B, and tigecycline, against six carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates. Drug interactions were interpreted using two models, that is, the fractional inhibitory concentration index (FICI) model and the percentage of growth difference (ΔE) model. The results show that a majority of the combination groups exhibited partial synergy and additive interactions, such as the combinations of carbapenems and cefoperazone-sulbactam (SCF) with ABH or AML. While the combination of PB/AML exhibited synergistic interactions against all tested isolates, and PB/ABH exhibited synergistic interactions against two isolates. The FICI and ΔE model correlated very well for the combinations of PBABH and PB/AML against AB2. The combinations of TGC with ABH or AML mainly exhibited additive and indifferent interactions. There were no antagonistic interactions observed in any of the combinations. In conclusion, this study revealed that the non-antibacterial agents ABH or AML can work synergistically or partial synergistically with antibacterial agents against CRAB. This finding is crucial for overcoming the carbapenem resistance of A. baumannii. SIGNIFICANCE AND IMPACT OF THE STUDY: Drug combination is an effective approach for the treatment of resistant bacterial infection. The significance of using drug combination is that it can reduce drug dosage requirements, reduce the toxic effects of agents and prevent or delay the emergence of drug resistance. This study measured the in vitro interactions between non-antimicrobial agents and antibacterial agents against carbapenem-resistant Acinetobacter baumannii and the results of this study provide new insight to find strategies to overcome the carbapenem resistance in A. baumannii.


Subject(s)
Acinetobacter baumannii/drug effects , Ambroxol/pharmacology , Amlodipine/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/genetics , Acinetobacter Infections/microbiology , Acinetobacter baumannii/genetics , Acinetobacter baumannii/growth & development , Carbapenems/pharmacology , Cefoperazone/pharmacology , Cilastatin, Imipenem Drug Combination/pharmacology , Drug Combinations , Drug Synergism , Humans , Meropenem/pharmacology , Microbial Sensitivity Tests , Sulbactam/pharmacology , Thienamycins/pharmacology
11.
Biochem Biophys Res Commun ; 523(1): 6-9, 2020 02 26.
Article in English | MEDLINE | ID: mdl-31822344

ABSTRACT

Tuberculosis has attracted increased attention worldwide due to its high morality and its resistance to treatment with traditional antibacterial drugs. The l,d-transpeptidase LdtMt2 confers resistance to traditional ß-lactams and is considered a target for anti-Tuberculosis treatment. Carbapenems are proposed to inhibit Mycobacterium tuberculosis by repressing the activity of LdtMt2. The interaction mechanisms between LdtMt2 and carbapenems have been revealed by LdtMt2-carbapenem adduct structures along with various biochemical assays. Interestingly, the lack of the 1-ß-methyl group in imipenem may be related to its high binding ability to LdtMt2. However, there is limited evidence on the interaction mode of LdtMt2 and panipenem, another carbapenem lacking the 1-ß-methyl group. Herein, we identified the biochemical features of panipenem binding to LdtMt2. We further suggest that the presence of the 1-ß-methyl group in carbapenems is indeed related to the ligand affinity of LdtMt2 and that the presence of the Y308 and Y318 residues in LdtMt2 stabilized the conformation of the LdtMt2-carbepenem adduct. Our research provides a structural basis for the development of novel carbapenems against L,D-transpeptidases.


Subject(s)
Enzyme Inhibitors/pharmacology , Peptidyl Transferases/antagonists & inhibitors , Thienamycins/pharmacology , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Peptidyl Transferases/chemistry , Peptidyl Transferases/metabolism , Thienamycins/chemistry
12.
Neuropharmacology ; 163: 107808, 2020 02.
Article in English | MEDLINE | ID: mdl-31706993

ABSTRACT

Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.


Subject(s)
Cannabidiol/pharmacology , Nociception/drug effects , Parkinson Disease/physiopathology , Amidohydrolases/antagonists & inhibitors , Analgesics/pharmacology , Animals , Benzamides/pharmacology , Brain/pathology , Capsaicin/analogs & derivatives , Capsaicin/pharmacology , Carbamates/pharmacology , Celecoxib/pharmacology , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Hyperalgesia/pathology , Male , Mice , Mice, Inbred C57BL , Morphine/pharmacology , Oxidopamine , Pain/drug therapy , Piperidines/pharmacology , Pyrazoles/pharmacology , Thienamycins/pharmacology
13.
Biomed Environ Sci ; 32(4): 235-241, 2019 Apr.
Article in English | MEDLINE | ID: mdl-31217059

ABSTRACT

OBJECTIVE: To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. METHODS: Biapenem/clavulanate (BP/CL) was evaluated for in vitro activity against Mycobacterium tuberculosis (Mtb) multidrug-resistant (MDR) isolates, extensively drug-resistant (XDR) isolates, and the H37RV strain. BP/CL activity against the H37Rv strain was assessed in liquid cultures, in macrophages, and in mice.. RESULTS: BP/CL exhibited activity against MDR and XDR Mtb isolates in liquid cultures. BP/CL treatment significantly reduced the number of colony forming units (CFU) of Mtb within macrophages compared with control untreated infected macrophages. Notably, BP/CL synergized in pairwise combinations with protionamide, aminosalicylate, and capreomycin to achieve a fractional inhibitory concentration for each pairing of 0.375 in vitro. In a mouse tuberculosis infection model, the efficacy of a cocktail of levofloxacin + pyrazinamide + protionamide + aminosalicylate against Mtb increased when the cocktail was combined with BP/CL, achieving efficacy similar to that of the positive control treatment (isoniazid + rifampin + pyrazinamide) after 2 months of treatment. CONCLUSION: BP/CL may provide a new option to clinically treat MDR tuberculosis.


Subject(s)
Anti-Infective Agents/therapeutic use , Mycobacterium tuberculosis/drug effects , Thienamycins/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapy , Animals , Anti-Infective Agents/pharmacology , Cell Line , Drug Evaluation, Preclinical , Macrophages , Mice , Thienamycins/pharmacology
14.
J Mol Recognit ; 32(8): e2781, 2019 08.
Article in English | MEDLINE | ID: mdl-31050067

ABSTRACT

The molecular recognition and interaction of CphA from Aeromonas hydrophila with imipenem (Imip) and biapenem (Biap) were studied by means of the combined use of fluorescence spectra and molecular docking. The results showed that both the fluorescence quenching of CphA by Imip and Biap were caused through the combined dynamic and static quenching, and the latter was dominating in the process; the microenvironment and conformational of CphA were altered upon the addition of Imip and Biap from synchronous and three-dimensional fluorescence. The binding of CphA with Imip or Biap caused a conformational change in the loop of CphA, and through the conformational change, the loop opened the binding pocket of CphA to allow for an induced fit of the newly introduced ligand. In the binding of CphA with Imip, the whole molecule entered into the active pocket of CphA. The binding was driven by enthalpy change, and the binding force between them was mainly hydrogen bonding and Van der Waals force; whereas in the binding of CphA with Biap, only the beta-lactam ring of Biap entered into the binding pocket of CphA while the side chain was located outside the active pocket. The binding was driven by the enthalpy change and entropy change together, and the binding force between them was mainly electrostatic interaction. This study provided an insight into the recognition and binding of CphA with antibiotics, which may be helpful for designing new substrate for beta-lactamase and developing new antibiotics resistant to superbugs.


Subject(s)
Aeromonas hydrophila/enzymology , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Imipenem/pharmacology , Thienamycins/pharmacology , beta-Lactamases/chemistry , beta-Lactamases/metabolism , Aeromonas hydrophila/chemistry , Binding Sites , Hydrogen Bonding , Hydrolysis , Imipenem/chemistry , Models, Molecular , Molecular Docking Simulation , Protein Binding , Protein Conformation , Spectrometry, Fluorescence , Thienamycins/chemistry
15.
J Infect Chemother ; 25(1): 75-77, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30100401

ABSTRACT

We determined the optimal antimicrobial in the sodium mercaptoacetic acid double disk synergy test (SMA-DDST) for the detection of IMP-1-producing Pseudomonas aeruginosa isolates in Japan and evaluated the performance of the test. Fifty-four P. aeruginosa clinical isolates were tested, including 39 IMP-1 producers and 15 non-metallo-ß-lactamase (MBL)-producing carbapenem- and ceftazidime (CAZ)-resistant isolates. The SMA-DDST was performed with CAZ, cefepime (CFPM), imipenem (IPM), meropenem (MEPM), doripenem (DRPM), or biapenem (BIPM)-containing disks. The sensitivity of the SMA-DDST with CAZ, CFPM, IPM, MEPM, DRPM, and BIPM was 39/39 (100%), 36/39 (92%), 18/39 (46%), 8/39 (21%), 19/39 (49%), and 36/39 (92%), respectively. The specificity was 15/15 (100%) for all SMA-DDSTs. This suggests that the isolates may have a resistance mechanism other than MBL production for IPM, MEPM, or DRPM. Since the CAZ resistance mechanism in P. aeruginosa is the same as that of CFPM, but differs from that of carbapenems, we conclude that combining CAZ with BIPM SMA-DDSTs can prevent any failure in the detection of IMP-1-producing P. aeruginosa.


Subject(s)
Anti-Bacterial Agents/pharmacology , Ceftazidime/pharmacology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/isolation & purification , Thienamycins/pharmacology , Thioglycolates/pharmacology , beta-Lactamases/metabolism , Drug Resistance, Multiple, Bacterial/drug effects , Drug Synergism , Humans , Japan , Sensitivity and Specificity
16.
Article in English | MEDLINE | ID: mdl-30420483

ABSTRACT

Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13-9001 specifically inhibits MexAB-OprM in Pseudomonas aeruginosa Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified, and these fell into two categories: those with alterations in the target MexB (F628L and ΔV177) and those with an alteration in a putative sensor kinase of unknown function, PA1438 (L172P). The alterations in MexB were consistent with reported structural studies of the D13-9001 interaction with MexB. The PA1438L172P alteration mediated a >150-fold upregulation of MexMN pump gene expression and a >50-fold upregulation of PA1438 and the neighboring response regulator gene, PA1437. We propose that these be renamed mmnR and mmnS for MexMN regulator and MexMN sensor, respectively. MexMN was shown to partner with the outer membrane channel protein OprM and to pump several ß-lactams, monobactams, and tazobactam. Upregulated MexMN functionally replaced MexAB-OprM to efflux these compounds but was insusceptible to inhibition by D13-9001. MmnSL172P also mediated a decrease in susceptibility to imipenem and biapenem that was independent of MexMN-OprM. Expression of oprD, encoding the uptake channel for these compounds, was downregulated, suggesting that this channel is also part of the MmnSR regulon. Transcriptome sequencing (RNA-seq) of cells encoding MmnSL172P revealed, among other things, an interrelationship between the regulation of mexMN and genes involved in heavy metal resistance.


Subject(s)
Piperidines/pharmacology , Pseudomonas aeruginosa/drug effects , Quaternary Ammonium Compounds/pharmacology , beta-Lactams/pharmacology , Imipenem/pharmacology , Microbial Sensitivity Tests , Monobactams/pharmacology , Pseudomonas aeruginosa/genetics , Tazobactam/pharmacology , Thienamycins/pharmacology , Transcriptome/genetics
17.
Proc Natl Acad Sci U S A ; 115(39): 9797-9802, 2018 09 25.
Article in English | MEDLINE | ID: mdl-30201715

ABSTRACT

Metabolically quiescent bacteria represent a large proportion of those in natural and host environments, and they are often refractory to antibiotic treatment. Such drug tolerance is also observed in the laboratory during stationary phase, when bacteria face stress and starvation-induced growth arrest. Tolerance requires (p)ppGpp signaling, which mediates the stress and starvation stringent response (SR), but the downstream effectors that confer tolerance are unclear. We previously demonstrated that the SR is linked to increased antioxidant defenses in Pseudomonas aeruginosa We now demonstrate that superoxide dismutase (SOD) activity is a key factor in SR-mediated multidrug tolerance in stationary-phase P. aeruginosa Inactivation of the SR leads to loss of SOD activity and decreased multidrug tolerance during stationary phase. Genetic or chemical complementation of SOD activity of the ΔrelA spoT mutant (ΔSR) is sufficient to restore antibiotic tolerance to WT levels. Remarkably, we observe high membrane permeability and increased drug internalization upon ablation of SOD activity. Combined, our results highlight an unprecedented mode of SR-mediated multidrug tolerance in stationary-phase P. aeruginosa and suggest that inhibition of SOD activity may potentiate current antibiotics.


Subject(s)
Drug Resistance, Multiple, Bacterial , Pseudomonas aeruginosa/drug effects , Superoxide Dismutase/metabolism , Anti-Bacterial Agents/pharmacology , Dose-Response Relationship, Drug , Gentamicins/pharmacology , Ligases/metabolism , Meropenem , Microbial Sensitivity Tests , Ofloxacin/pharmacology , Pseudomonas aeruginosa/enzymology , Signal Transduction , Superoxide Dismutase/physiology , Thienamycins/pharmacology
18.
Eur J Med Chem ; 155: 285-302, 2018 Jul 15.
Article in English | MEDLINE | ID: mdl-29894943

ABSTRACT

The worldwide prevalence of NDM-1-producing bacteria has drastically undermined the clinical efficacy of the last line antibiotic of carbapenems, prompting a need to devise effective strategy to preserve their clinical value. Our previous studies have shown that ebselen can restore the efficacy of meropenem against a laboratory strain that produces NDM-1. Here we report the construction of a focused compound library of 1,2-benzisoselenazol-3(2H)-one derivatives which comprise a total of forty-six candidate compounds. The structure-activity relationship of these compounds and their potential to serve as an adjuvant to enhance the antimicrobial efficacy of meropenem against a collection of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae isolates was examined. Drug combination assays indicated that these derivatives exhibited synergistic antimicrobial activity when used along with meropenem, effectively restoring the activity of carbapenems against the resistant strains tested in a Galleria mellonella larvae in vivo infection model. The mode of inhibition of one compound, namely 11_a38, which was depicted when tested on the purified NDM-1 enzyme, indicated that it could covalently bind to the enzyme and displaced one zinc ion from the active site. Overall, this study provides a novel 1,2-benzisoselenazol-3(2H)-one scaffold that exhibits strong synergistic antimicrobial activity with carbapenems, and low cytotoxicity. The prospect of application of such compounds as carbapenem adjuvants warrants further evaluation.


Subject(s)
Anti-Bacterial Agents/pharmacology , Carbapenem-Resistant Enterobacteriaceae/drug effects , Organoselenium Compounds/pharmacology , Thienamycins/pharmacology , beta-Lactamases/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Carbapenem-Resistant Enterobacteriaceae/isolation & purification , Carbapenem-Resistant Enterobacteriaceae/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , HeLa Cells , Humans , Meropenem , Molecular Structure , Organoselenium Compounds/chemistry , Structure-Activity Relationship , Thienamycins/chemistry
20.
Anaerobe ; 52: 9-15, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29860038

ABSTRACT

Knowledge about the antimicrobial susceptibility patterns of different Prevotella species is limited. The aim of this study was to determine the current antimicrobial susceptibility of clinical isolates of Prevotella species from different parts of Europe, Kuwait and Turkey. Activity of 12 antimicrobials against 508 Prevotella isolates, representing 19 species, were tested according to Etest methodology. EUCAST, CLSI and FDA guidelines were used for susceptibility interpretations. All Prevotella species were susceptible to piperacillin/tazobactam, imipenem, meropenem, tigecycline and metronidazole. Ampicillin/sulbactam and cefoxitin also showed good activity. Ampicillin, clindamycin, tetracycline and moxifloxacin were less active; 51.2%, 33.7%, 36.8% and 18.3% of isolates were non-susceptible, respectively. A total of 49 (9.6%) isolates were resistant to three or more antimicrobials. Prevotella bivia was the most prevalent species (n = 118) and accounted for most of the multidrug-resistant isolates. In conclusion, the level of non-susceptibility to antimicrobials, which may be used for treatment of infections involving Prevotella species, are a cause of concern. This data emphasizes the need for species level identification of clinical Prevotella isolates and periodic monitoring of their susceptibility to guide empirical treatment.


Subject(s)
Anti-Bacterial Agents/pharmacology , Disk Diffusion Antimicrobial Tests/methods , Prevotella/drug effects , Ampicillin/pharmacology , Bacteroidaceae Infections/microbiology , Clindamycin/pharmacology , Fluoroquinolones/pharmacology , Humans , Kuwait , Meropenem , Metronidazole/pharmacology , Moxifloxacin , Prevotella/growth & development , Prevotella/isolation & purification , Sulbactam/pharmacology , Thienamycins/pharmacology , Turkey
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