Aminoglycoside-Induced Nephrotoxicity

Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria. The most commonly utilized parenteral agents in this class include gentamicin, tobramycin and amikacin. Aminoglycosides are concentration-dependent, bactericidal agents that undergo active transport into the cell where they inhibit protein synthesis on the 30S subunit of the bacterial ribosome. As the use of aminoglycosides became more widespread, the toxic effects of these agents, most notably ototoxicity and nephrotoxicity, became more apparent. When other, safer, antimicrobial agents became available, the use of aminoglycosides sharply declined. The development of multi-drug resistance among bacteria has now lead clinicians to reexamine the role of the aminoglycosides in the treatment of serious infections. This review will revisit the mechanism and risk factors for the development of aminoglycoside-induced nephrotoxicity, as well as strategies to prevent patients from developing nephrotoxicity.

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Escherichia Coli Isolate From Hospital Sewage Is Carrying blaNDM-1 and blaoxa-10

10.21203/rs.3.rs-380303/v1 ◽

2021 ◽

Author(s):

Zimeng Hu ◽

Weiye Chen ◽

Genglin Guo ◽

Chen Dong ◽

Yun Shen ◽

...

Keyword(s):

Escherichia Coli ◽

Drug Resistance ◽

Hospital Environment ◽

Multi Drug Resistance ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Drug Resistant Bacteria ◽

Hospital Sewage

Abstract Carbapenems, as the “last line of defense” against gram-negative bacteria, are increasingly being challenged by drug-resistant bacteria, especially in Enterobacteriaceae. In this study, a carbapenems resistant gram-negative bacterium, named AH001, was isolated from hospital sewage, and modified Hoge test confirmed this bacterium can produce carbapenemase. Further analysis revealed that this bacterium is multi-drug resistance, which against additional seven antibiotics. Whole-genome sequencing and analysis showed that AH001 could not be classified by existing MLST, and its serotype couldn’t be distinguished among O9, O89 or O168 in O antigen prediction. More attention should be paid to the role of environmental source Escherichia coli in the development and transfer of drug resistance in the hospital environment.

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Carbapenem Resistance in Gram-negative Bacteria in South-western Nigeria: The Role of Extended-spectrum β-lactamase CTX-M-15

West Indian Medical Journal ◽

10.7727/wimj.2017.122 ◽

2018 ◽

pp. 344-349

Author(s):

Do Ogbolu ◽

Ma Webber

Keyword(s):

Outer Membrane ◽

Antimicrobial Agents ◽

Random Amplified Polymorphic Dna ◽

Outer Membrane Proteins ◽

Carbapenem Resistance ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Carbapenem Resistant ◽

Extended Spectrum

Objective: To determine the role of extended-spectrum β-lactamases in carbapenem-resistant Gram-negative bacteria from south-western Nigeria. Methods: Twenty-seven carbapenem-resistant isolates that were found to be non-carbapenemase producers (15 Escherichia coli, 9 Klebsiella pneumoniae and 3 Pseudomonas aeruginosa) were further studied. These isolates were subjected to analysis including phenotypic and genotypic detection of various β-lactamases, efflux activity, outer membrane protein, plasmids replicon typing, detection of transferable genes and resistances and typing using random amplified polymorphic DNA tests. Results: No isolates demonstrated de-repression of efflux, but all showed either complete loss or reduced production of outer membrane proteins. Transconjugants from these strains contained various genes including plasmid-mediated quinolone resistance and extended-spectrum beta-lactamases. All the transconjugants carried the blaCTX-M-15 gene. The transconjugants had varying minimum inhibitory concentrations of carbapenems ranging from 0.03 μg/ml to 8 μg/ml. Varying resistances to other antimicrobial agents were also transferred with the plasmids. The donor isolates were not clonally related by molecular typing. Conclusion: Resistance to carbapenem antibiotics in this sample was not mediated only by carbapenemases but also by production of extended-spectrum β-lactamases (largely CTX-M-15), accompanied by protein loss. This was an important mechanism underpinning carbapenem resistance in these clinical isolates of various species.

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Electrophysiological Characterization of Transport Across Outer Membrane Channels from Gram-Negative Bacteria in Their Native Environment

10.26434/chemrxiv.8282204.v2 ◽

2019 ◽

Author(s):

Jiajun Wang ◽

Rémi Terrasse ◽

Jayesh Arun Bafna ◽

Lorraine Benier ◽

Mathias Winterhalter

Keyword(s):

Outer Membrane ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Multi Drug Resistance ◽

Gram Negative Bacteria ◽

Membrane Channels ◽

Gram Negative ◽

E Coli ◽

Electrophysiological Characterization

Multi-drug-resistance in Gram-negative bacteria is often associated with low permeability of outer membrane. To investigate the role of membrane protein channels in the passage of antibiotics, we extract, purify, reconstitute them into artificial bilayer. Here we demonstrate that using a fusion of native outer membrane vesicles (OMV) facilitates channel reconstitution into bilayer and allows to characterize them in their native environment. Proteins from E. coli (OmpF, OmpC) were overexpressed from the host, and the corresponding OMVs were collected. Each OMV fusion revealed surprisingly only a few channel activities. The asymmetry of the OMV translates after fusion into bilayer with the LPS dominantly present at OMV addition side. Compared to conventional methods, channels fused from OMVs have similar conductance but broader distribution. The further addition of Enrofloxacin yielded higher association but lower dissociation rates attribute to the presence of LPS. We conclude using OMV is a robust approach for functional and structural studies of membrane channels in the native membrane.

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Emerging Resistance of Gram Negative Pathogens in Community-Acquired Pneumonia

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0040-1709137 ◽

2020 ◽

Vol 41 (04) ◽

pp. 480-495

Author(s):

Francesco Amati ◽

Marcos I. Restrepo

Keyword(s):

Risk Factors ◽

Geographical Location ◽

Diagnostic Techniques ◽

Community Acquired Pneumonia ◽

Clinical Severity ◽

Molecular Testing ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Local Ecology

AbstractIn recent decades, there has been a growing interest about the role of gram negative bacteria in community-acquired pneumonia (CAP), especially Pseudomonas aeruginosa, Enterobacteriaceae, and Acinetobacter baumannii. The prevalence of these pathogens differs largely according to the local ecology and the geographical location. Identifying gram negative bacteria, and in particular resistant gram negative bacteria, is of paramount importance in patients with CAP because these pathogens are associated with higher clinical severity and unfavorable outcomes. The use of individualized risk factors to predict each pathogen is a helpful strategy that needs to be locally validated. However, it should be taken into account that most of the risk factors identified in the literature are heterogeneously defined or lack consistency. New diagnostic techniques, such as molecular testing, are promising methods for early detection of these gram negative pathogens. The increasing mechanisms of resistance to antibiotics of these pathogens have limited our therapeutic approach. This narrative review focuses on the epidemiology, risk factors, diagnosis, and therapeutic options for the most relevant gram negative bacteria that cause CAP.

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Prevalence of Gram Negative Infections by Acinetobacter and Pseudomonas Severely Resistant to Antibiotic Susceptibility Based on Minimum Growth Inhibitor Concentration

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2019/v29i330235 ◽

2019 ◽

pp. 1-6

Author(s):

Sahar Defaee ◽

Maryam Farasatinasab ◽

Mahin Jamshidi Makani ◽

Hooman Rahimipour ◽

Pouyan Alinia ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibiotic Treatment ◽

Antimicrobial Agents ◽

Growth Inhibitor ◽

Multi Drug Resistance ◽

Gram Negative Bacteria ◽

Inhibitor Concentration ◽

Gram Negative ◽

The World ◽

Pseudomonas Species

Introduction: Currently, we are witnessing the formation of various species of gram-negative microorganisms, including Enterobacteriaceae, Pseudomonas aeruginosa and acinetobacter, resistant to antibiotics such as MDR, XDR and PDR. This study is important to confirm microbial resistance to an antimicrobial agent and also to monitor the activity of new antimicrobial agents. Regarding XDR gram-negative microorganisms isolated from samples, it was considered necessary to determine MIC. Methods: Patients suspected of various infections with septicemia diagnosed in different wards of the Firoozgar Hospital were enrolled. The quantitative value of minimum growth inhibitor concentration (MIC) was determined for infections caused by highly resistant gram-negative bacteria (acinetobacter and Pseudomonas species) (XDR) reported by antibiogram disk. Results: sample size was 117, of which 41.9% were female and 58.1% were male. Regarding Colistin, 80% of the cultures were resistant and 12% were intermittent; this value was 52% in the MIC test. Regarding tigecycline, 100% of the acinetobacter samples were susceptible to this antibiotic. Most of cultures which had antibiotic resistance were acinetobacter (61.4%) and pseudomonas (39.6%). Discussion: Acinetobacter baumannii is susceptible to tigecycline. Emergence of multi-drug resistance in Pseudomonas aeruginosa and A. baumannii is a major concern in the world, because several drugs, except polymyxins, are available to treat these infections. A significant resistance was found in MIC to Colistin (31.1%). Thus, there is resistance to Colistin, which is one of the last lines of antibiotic treatment. Conclusion: This study shows an increase in percentage resistance of these bacteria to antibiotics. This trend is a worrying process for antibiotic treatment of diseases.

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Functional Characterization of a Novel Hybrid Peptide with High Potency against Gram-negative Bacteria

Current Pharmaceutical Design ◽

10.2174/1381612826666200128090700 ◽

2020 ◽

Vol 26 (3) ◽

pp. 376-385 ◽

Cited By ~ 1

Author(s):

Yara Al Tall ◽

Baha’a Al-Rawashdeh ◽

Ahmad Abualhaijaa ◽

Ammar Almaaytah ◽

Majed Masadeh ◽

...

Keyword(s):

Antimicrobial Agents ◽

Functional Characterization ◽

Antimicrobial Activities ◽

Health Concern ◽

Multi Drug Resistance ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Hybrid Peptide ◽

Gram Negative ◽

Human Red Blood Cells

Background: Multi-drug resistant infections are a growing worldwide health concern. There is an urgent need to produce alternative antimicrobial agents. Objective : The study aimed to design a new hybrid antimicrobial peptide, and to evaluate its antimicrobial activity alone and in combination with traditional antibiotics. Methods: Herein, we designed a novel hybrid peptide (BMR-1) using the primary sequences of the parent peptides Frog Esculentin-1a and Monkey Rhesus cathelicidin (RL-37). The positive net charge was increased, and other physicochemical parameters were optimized. The antimicrobial activities of BMR-1 were tested against control and multi-drug resistant gram-negative bacteria. Results: BMR-1 adopted a bactericidal behavior with MIC values of 25-30 µM. These values reduced by over 75% upon combination with conventional antibiotics (levofloxacin, chloramphenicol, ampicillin, and rifampicin). The combination showed strong synergistic activities in most cases and particularly against multi-drug resistance P. aeruginosa and E. coli. BMR-1 showed similar potency against all tested strains regardless of their resistant mechanisms. BMR-1 exhibited no hemolytic effect on human red blood cells with the effective MIC values against the tested strains. Conclusion: BMR-1 hybrid peptide is a promising candidate to treat resistant infectious diseases caused by gramnegative bacteria.

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Electrophysiological Characterization of Transport Across Outer Membrane Channels from Gram-Negative Bacteria in Their Native Environment

10.26434/chemrxiv.8282204 ◽

2019 ◽

Author(s):

Jiajun Wang ◽

Rémi Terrasse ◽

Jayesh Arun Bafna ◽

Lorraine Benier ◽

Mathias Winterhalter

Keyword(s):

Outer Membrane ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Multi Drug Resistance ◽

Gram Negative Bacteria ◽

Membrane Channels ◽

Gram Negative ◽

E Coli ◽

Electrophysiological Characterization

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Electrophysiological Characterization of Transport Across Outer Membrane Channels from Gram-Negative Bacteria in Their Native Environment

10.26434/chemrxiv.8282204.v1 ◽

2019 ◽

Author(s):

Jiajun Wang ◽

Rémi Terrasse ◽

Jayesh Arun Bafna ◽

Lorraine Benier ◽

Mathias Winterhalter

Keyword(s):

Outer Membrane ◽

Lipid Membrane ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Multi Drug Resistance ◽

Gram Negative Bacteria ◽

Membrane Channels ◽

Gram Negative ◽

Electrophysiological Characterization

Multi-drug resistance in Gram-negative bacteria is often associated with low permeability of the outer membrane. To investigate the role of membrane channels in the uptake of antibiotics, we extract, purify and reconstitute them into artificial planar membranes. To avoid this time-consuming procedure, here we show a robust approach using fusion of native outer membrane vesicles (OMV) into planar lipid bilayer which moreover allows also to some extend the characterization of membrane protein channels in their native environment. Two major membrane channels from Escherichia coli, OmpF and OmpC, were overexpressed from the host and the corresponding OMVs were collected. Each OMV fusion revealed surprisingly single or only few channel activities. The asymmetry of the OMV´s translates after fusion into the lipid membrane with the LPS dominantly present at the side of OMV addition. Compared to conventional reconstitution methods, the channels fused from OMVs containing LPS have similar conductance but a much broader distribution. The addition of Enrofloxacin on the LPS side yields somewhat higher association (kon) and lower dissociation (koff) rates compared to LPS-free reconstitution. We conclude that using outer membrane vesicles is a fast and easy approach for functional and structural studies of membrane channels in the native membrane.

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Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666191223110518 ◽

2020 ◽

Vol 20 (3) ◽

pp. 192-208 ◽

Cited By ~ 1

Author(s):

Talita Odriane Custodio Leite ◽

Juliana Silva Novais ◽

Beatriz Lima Cosenza de Carvalho ◽

Vitor Francisco Ferreira ◽

Leonardo Alves Miceli ◽

...

Keyword(s):

In Silico ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Mass Spectrometry Analysis ◽

World Health ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Dione Derivative ◽

In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

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Super-Cationic Peptide Dendrimers—Synthesis and Evaluation as Antimicrobial Agents

Antibiotics ◽

10.3390/antibiotics10060695 ◽

2021 ◽

Vol 10 (6) ◽

pp. 695

Author(s):

Estelle J. Ramchuran ◽

Isabel Pérez-Guillén ◽

Linda A. Bester ◽

René Khan ◽

Fernando Albericio ◽

...

Keyword(s):

Antibacterial Agent ◽

Antimicrobial Agents ◽

Health Concern ◽

Gram Negative Bacteria ◽

Cationic Peptide ◽

Public Health Concern ◽

Gram Negative ◽

Peptide Dendrimers ◽

Microbial Infections ◽

Lead Candidate

Microbial infections are a major public health concern. Antimicrobial peptides (AMPs) have been demonstrated to be a plausible alternative to the current arsenal of drugs that has become inefficient due to multidrug resistance. Herein we describe a new AMP family, namely the super-cationic peptide dendrimers (SCPDs). Although all members of the series exert some antibacterial activity, we propose that special attention should be given to (KLK)2KLLKLL-NH2 (G1KLK-L2KL2), which shows selectivity for Gram-negative bacteria and virtually no cytotoxicity in HepG2 and HEK293. These results reinforce the validity of the SCPD family as a valuable class of AMP and support G1KLK-L2KL2 as a strong lead candidate for the future development of an antibacterial agent against Gram-negative bacteria.

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