scholarly journals Multiscale simulations identify origins of differential carbapenem hydrolysis by the OXA-48 β-lactamase

2021 ◽  
Author(s):  
Viivi Hirvonen ◽  
Tal Moshe Weizmann ◽  
Adrian Mulholland ◽  
James Spencer ◽  
Marc van der Kamp
Keyword(s):  
Water Molecule ◽  
Bacterial Infections ◽  
Enzyme Reaction ◽  
Subtle Change ◽  
Conformational Substates ◽  
Multi Scale ◽  
Hydrogen Bonding Pattern ◽  
Carbapenem Resistant ◽  
New Antibiotics ◽  
Healthcare Associated

OXA-48 β-lactamases are frequently encountered in bacterial infections caused by carbapenem-resistant Gram-negative bacteria. Due to the importance of carbapenems in treatment of healthcare-associated infections, and the increasingly wide dissemination of OXA-48-like enzymes on plasmids, these β-lactamases are of high clinical significance. Notably, OXA-48 hydrolyses imipenem more efficiently than other commonly used carbapenems, such as meropenem. Here, we use extensive multi-scale simulations of imipenem and meropenem hydrolysis by OXA-48 to dissect the dynamics and to explore differences in reactivity of the possible conformational substates of the respective acylenzymes. QM/MM simulations of the deacylation reaction for both substrates demonstrate that deacylation is favoured when the 6α-hydroxyethyl group is able to hydrogen bond to the water molecule responsible for deacylation, but disfavoured by increasing hydration of either oxygen of the carboxylated Lys73 general base. Differences in free energy barriers calculated from the QM/MM simulations correlate well with the experimentally observed differences in hydrolytic efficiency between meropenem and imipenem. We conclude that the impaired breakdown of meropenem, compared to imipenem, which arises from a subtle change in the hydrogen bonding pattern between the deacylating water molecule and the antibiotic, is most likely induced by the meropenem 1-methyl group. In addition to increased insights into carbapenem breakdown by OXA β-lactamases, which may aid design of new antibiotics or inhibitors, our approach exemplifies the combined use of atomistic simulations in determining the possible different enzyme-substrate substates, and their influence on enzyme reaction kinetics.

scholarly journals 1,4,7-Triazacyclononane Restores the Activity of β-Lactam Antibiotics against Metallo-β-Lactamase-Producing Enterobacteriaceae: Exploration of Potential Metallo-β-Lactamase Inhibitors

2018 ◽  
Vol 85 (3) ◽  
Author(s):  
Anou M. Somboro ◽  
Daniel G. Amoako ◽  
John Osei Sekyere ◽  
Hezekiel M. Kumalo ◽  
René Khan ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Bacterial Infections ◽  
World Health ◽  
Health Concern ◽  
Computational Studies ◽  
Synergistic Activity ◽  
Carbapenem Resistant ◽  
Catalytic Active Site ◽  
Significant Public Health ◽  
New Antibiotics

ABSTRACT Metallo-β-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-β-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available β-lactams are thus imperative. We investigated a zinc-chelating moiety, 1,4,7-triazacyclononane (TACN), for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae. MICs, minimum bactericidal concentrations (MBCs), the serum effect, fractional inhibitory concentration indexes, and time-kill kinetics were determined using broth microdilution techniques according to Clinical and Laboratory Standards Institute (CSLI) guidelines. Enzyme kinetic parameters and the cytotoxic effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from between 8 and 64 mg/liter to 0.03 mg/liter in the presence of TACN. The TACN-meropenem combination showed bactericidal effects with an MBC/MIC ratio of ≤4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be noncytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active-site pockets. This was supported by its inhibition constant (Ki), which was 0.044 μM, and its inactivation constant (Kinact), which was 0.0406 min−1, demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor. IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported to be critical in the World Health Organization’s priority pathogens list for the research and development of new antibiotics. CRE produce enzymes, such as metallo-β-lactamases (MBLs), which inactivate β-lactam antibiotics. Combination therapies involving a β-lactam antibiotic and a β-lactamase inhibitor remain a major treatment option for infections caused by β-lactamase-producing organisms. Currently, no MBL inhibitor–β-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the activity of carbapenem. This study demonstrates that TACN inhibits MBLs efficiently and holds promises as a potential MBL inhibitor to help curb the global health threat posed by MBL-producing CREs.

scholarly journals Carbapenem-Resistant Gram-Negative Bacterial Infections in Children

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
David Aguilera-Alonso ◽  
Luis Escosa-García ◽  
Jesús Saavedra-Lozano ◽  
Emilia Cercenado ◽  
Fernando Baquero-Artigao
Keyword(s):  
Bacterial Infections ◽  
Pediatric Patients ◽  
Current Knowledge ◽  
Pediatric Population ◽  
Safety Data ◽  
Global Public Health ◽  
Comprehensive Review ◽  
Carbapenem Resistant ◽  
New Antibiotics ◽  
Almost All

ABSTRACT Carbapenem-resistant organisms (CRO) are a major global public health threat. Enterobacterales hydrolyze almost all β-lactams through carbapenemase production. Infections caused by CRO are challenging to treat due to the limited number of antimicrobial options. This leads to significant morbidity and mortality. Over the last few years, several new antibiotics effective against CRO have been approved. Some of them (e.g., plazomicin or imipenem-cilastatin-relebactam) are currently approved for use only by adults; others (e.g., ceftazidime-avibactam) have recently been approved for use by children. Recommendations for antibiotic therapy of CRO infections in pediatric patients are based on evidence mainly from adult studies. The availability of pediatric pharmacokinetic and safety data is the cornerstone to broaden the use of proposed agents in adults to the pediatric population. This article provides a comprehensive review of the current knowledge regarding infections caused by CRO with a focus on children, which includes epidemiology, risk factors, outcomes, and antimicrobial therapy management, with particular attention being given to new antibiotics.

scholarly journals Antimicrobial resistance conferred by OXA-48 β-lactamases:towards a detailed mechanistic understanding

2021 ◽  
Author(s):  
Viivi H. A. Hirvonen ◽  
James Spencer ◽  
Marc W. van der Kamp
Keyword(s):  
Bacterial Infections ◽  
Gram Negative Bacteria ◽  
Carbapenem Resistant ◽  
Open Research ◽  
Resistance To Penicillin ◽  
Research Questions ◽  
Mechanistic Basis ◽  
Healthcare Associated ◽  
The Relationship ◽  
Detailed Picture

OXA-48-type β-lactamases are now routinely encountered in bacterial infections caused by carbapenem-resistant Enterobacterales. These enzymes are of high and growing clinical significance due to the importance of carbapenems in treatment of healthcare-associated infections by Gram-negative bacteria, the wide and increasing dissemination of OXA-48 enzymes on plasmids, and the challenges posed by their detection. OXA-48 confers resistance to penicillin (which is efficiently hydrolyzed) and carbapenem antibiotics (more slowly broken down). In addition to the parent enzyme, a growing array of variants of OXA-48 is now emerging. The spectrum of activity of these variants varies, with some hydrolyzing expanded-spectrum oxyimino-cephalosporins. The growth in importance and diversity of the OXA-48 group has motivated increasing numbers of studies that aim to elucidate the relationship between structure and specificity and establish the mechanistic basis for β-lactam turnover in this enzyme family. In this review we collate recently published structural, kinetic, and mechanistic information on the interactions between clinically relevant β-lactam antibiotics and inhibitors with OXA-48 β-lactamases. Collectively, these studies are starting to form a detailed picture of the underlying bases for the differences in β-lactam specificity between OXA-48 variants, and the consequent differences in resistance phenotype. We focus specifically on aspects of carbapenemase and cephalosporinase activities of OXA-48 β-lactamases and discuss β-lactamase inhibitor development in this context. Throughout the review, we also outline key open research questions for future investigation.

scholarly journals 1591. Antibiotic Utilization Trends in Veterans Affairs (VA) Patients with Carbapenem Resistant Enterobacteriaceae (CRE) Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S792-S792
Author(s):  
Alfredo Traversa ◽  
Linda Poggensee ◽  
Geneva M Wilson ◽  
Katie J Suda ◽  
Charlesnika T Evans ◽  
...  
Keyword(s):  
Treatment Options ◽  
Blood Stream ◽  
Chi Square ◽  
Blood Stream Infections ◽  
Exact Test ◽  
Carbapenem Resistant ◽  
Extended Spectrum ◽  
New Antibiotics ◽  
Chi Square Test ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Background Carbapenem-resistant Enterobacteriaceae (CRE) are classified as an “urgent threat” to public health. Historically, colistin and tigecycline had been considered the drugs of choice for CRE infections, while other agents such as aminoglycosides and carbapenems had been used as adjunctive therapy. However, the FDA approval of ceftazidime-avibactam in 2015, meropenem-vaborbactam in 2017, and plazomicin in 2018 has expanded treatment options. Our purpose was to assess trends in CRE treatment for “new” antibiotics (ceftazidime-avibactam, meropenem-vaborbactam, plazomicin) as compared with other antibiotics with CRE activity. Methods This was a retrospective cohort study describing treatment of CRE blood stream infections (BSI) across 134 VA facilities from 2012-2018. Patients were censored at their first positive blood culture with CRE. Categorical data was assessed with a Fisher’s exact test or chi-square test. Trends test and logistic regression were used to describe changes in CRE treatment over time. Results 724 patients with positive blood cultures for CRE were identified during the study period. Most patients were male (94%), white (32%) or Hispanic (38%), and the mean age was 71.5+11.9. Of those patients that received antibiotics (N=697), 53.4% carbapenems, 40.3% received aminoglycosides, 39.3% received polymyxins, 32.9% penicillins, 32.6% extended spectrum cephalosporins, 26.1% fluoroquinolones, 11.6% ceftazidime/avibactam, and 0.4% ceftolazone/tazobactam. Over the study period, there was decreased utilization of aminoglycosides (P < 0.0026) and colistin (P< 0.002) and increases in extended spectrum cephalosporins (P < 0.001) and ceftazidime/avibactam (P < 0.001). Conclusion Utilization of “older” agents such as aminoglycosides and polymyxins for the treatment of CRE blood stream infections is decreasing in the VA. Treating CRE with ceftazidime/avibactam, a newly approved antibiotic, and extended spectrum cephalosporins are increasing. Disclosures All Authors: No reported disclosures

scholarly journals Loxosceles gaucho Spider Venom: An Untapped Source of Antimicrobial Agents

Toxins ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 522 ◽  
Author(s):  
Paula Segura-Ramírez ◽  
Pedro Silva Júnior
Keyword(s):  
Bacterial Infections ◽  
High Performance ◽  
Antimicrobial Agents ◽  
Chemical Properties ◽  
Carcinoma Cells ◽  
Promising Candidate ◽  
Human Red Blood Cells ◽  
New Antibiotics ◽  
Conventional Antibiotics ◽  
Human Cervical Carcinoma Cells

The remarkable ability of microorganisms to develop resistance to conventional antibiotics is one of the biggest challenges that the pharmaceutical industry currently faces. Recent studies suggest that antimicrobial peptides discovered in spider venoms may be useful resources for the design of structurally new anti-infective agents effective against drug-resistant microorganisms. In this work, we found an anionic antibacterial peptide named U1-SCRTX-Lg1a in the venom of the spider Loxosceles gaucho. The peptide was purified using high-performance liquid chromatography (HPLC), its antimicrobial activity was tested through liquid growth inhibition assays, and its chemical properties were characterized using mass spectrometry. U1-SCRTX-Lg1a was found to show a monoisotopic mass of 1695.75 Da, activity against Gram-negative bacteria, a lack of hemolytic effects against human red blood cells, and a lack of cytotoxicity against human cervical carcinoma cells (HeLa). Besides this, the sequence of the peptide exhibited great similarity to specific regions of phospholipases D from different species of Loxosceles spiders, leading to the hypothesis that U1-SCRTX-Lg1a may have originated from a limited proteolytic cleavage. Our data suggest that U1-SCRTX-Lg1a is a promising candidate for the development of new antibiotics that could help fight bacterial infections and represents an exciting discovery for Loxosceles spiders.

scholarly journals Complete Genome Sequence of Pseudomonas aeruginosa K34-7, a Carbapenem-Resistant Isolate of the High-Risk Sequence Type 233

2018 ◽  
Vol 7 (4) ◽  
Author(s):  
George Taiaroa ◽  
Ørjan Samuelsen ◽  
Tom Kristensen ◽  
Ole Andreas Løchen Økstad ◽  
Adam Heikal
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Risk ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Sequence Type ◽  
Resistant Isolate ◽  
Content Type ◽  
Carbapenem Resistant ◽  
New Antibiotics

Carbapenem-resistant Pseudomonas aeruginosa is defined as a “critical” priority pathogen for the development of new antibiotics. Here we report the complete genome sequence of an extensively drug-resistant, Verona integron-encoded metallo-β-lactamase-expressing isolate belonging to the high-risk sequence type 233.

scholarly journals Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections

2019 ◽  
Vol 63 (6) ◽  
pp. 2789-2801 ◽  
Author(s):  
Bin Liu ◽  
Robert E. Lee Trout ◽  
Guo-Hua Chu ◽  
Daniel McGarry ◽  
Randy W. Jackson ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Infections ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

scholarly journals Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

2018 ◽  
Vol 14 ◽  
pp. 2881-2896 ◽  
Author(s):  
Laura Carro
Keyword(s):  
Protein Interactions ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Protein Protein Interactions ◽  
Lead Discovery ◽  
Antibiotic Development ◽  
Cellular Processes ◽  
Ppi Networks ◽  
New Antibiotics

Antibiotics are potent pharmacological weapons against bacterial infections; however, the growing antibiotic resistance of microorganisms is compromising the efficacy of the currently available pharmacotherapies. Even though antimicrobial resistance is not a new problem, antibiotic development has failed to match the growth of resistant pathogens and hence, it is highly critical to discover new anti-infective drugs with novel mechanisms of action which will help reducing the burden of multidrug-resistant microorganisms. Protein–protein interactions (PPIs) are involved in a myriad of vital cellular processes and have become an attractive target to treat diseases. Therefore, targeting PPI networks in bacteria may offer a new and unconventional point of intervention to develop novel anti-infective drugs which can combat the ever-increasing rate of multidrug-resistant bacteria. This review describes the progress achieved towards the discovery of molecules that disrupt PPI systems in bacteria for which inhibitors have been identified and whose targets could represent an alternative lead discovery strategy to obtain new anti-infective molecules.

scholarly journals An overview of carbapenem, its resistance and therapeutic options for infections caused by carbapenem resistant bacteria

2020 ◽  
Vol 9 (9) ◽  
pp. 1454
Author(s):  
Hari P. Nepal ◽  
Rama Paudel
Keyword(s):  
Bacterial Infections ◽  
Carbapenem Resistance ◽  
Therapeutic Options ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Beta Lactam ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
Carbapenem Resistant ◽  
The World

Carbapenems are beta-lactam drugs that have broadest spectrum of activity. They are commonly used as the drugs of last resort to treat complicated bacterial infections. They bind to penicillin binding proteins (PBPs) and inhibit cell wall synthesis in bacteria. Important members that are in clinical use include doripenem, ertapenem, imipenem, and meropenem. Unlike other members, imipenem is hydrolyzed significantly by renal dehydropeptidase; therefore, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin. Carbapenems are usually administered intravenously due to their low oral bioavailability. Most common side effects of these drugs include nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Increasing resistance to these antibiotics is being reported throughout the world and is posing a threat to public health.  Primary mechanisms of carbapenem resistance include expulsion of drug and inactivation of the drug by production of carbapenemases which may not only hydrolyze carbapenem, but also cephalosporin, penicillin, and aztreonam. Resistance especially among Gram negative bacteria is of much concern since there are only limited therapeutic options available for infections caused by carbapenem resistant Gram-negative bacterial pathogens. Commonly used drugs to treat such infections include polymyxins, fosfomycin and tigecycline.

scholarly journals Crumbling the Castle: Targeting DNABII Proteins for Collapsing Bacterial Biofilms as a Therapeutic Approach to Treat Disease and Combat Antimicrobial Resistance

Antibiotics ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 104
Author(s):  
James V. Rogers ◽  
Veronica L. Hall ◽  
Charles C. McOsker
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Defense Mechanism ◽  
Treatment Options ◽  
Bacterial Biofilms ◽  
Host Immune System ◽  
New Antibiotics ◽  
Financial Burdens ◽  
Global Threat

Antimicrobial resistance (AMR) is a concerning global threat that, if not addressed, could lead to increases in morbidity and mortality, coupled with societal and financial burdens. The emergence of AMR bacteria can be attributed, in part, to the decreased development of new antibiotics, increased misuse and overuse of existing antibiotics, and inadequate treatment options for biofilms formed during bacterial infections. Biofilms are complex microbiomes enshrouded in a self-produced extracellular polymeric substance (EPS) that is a primary defense mechanism of the resident microorganisms against antimicrobial agents and the host immune system. In addition to the physical protective EPS barrier, biofilm-resident bacteria exhibit tolerance mechanisms enabling persistence and the establishment of recurrent infections. As current antibiotics and therapeutics are becoming less effective in combating AMR, new innovative technologies are needed to address the growing AMR threat. This perspective article highlights such a product, CMTX-101, a humanized monoclonal antibody that targets a universal component of bacterial biofilms, leading to pathogen-agnostic rapid biofilm collapse and engaging three modes of action—the sensitization of bacteria to antibiotics, host immune enablement, and the suppression of site-specific tissue inflammation. CMTX-101 is a new tool used to enhance the effectiveness of existing, relatively inexpensive first-line antibiotics to fight infections while promoting antimicrobial stewardship.

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