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 TACN (1, 4, 7-Triazacyclononane) restores the activity of β-lactam antibiotics against Metallo-β-Lactamase producing Enterobacteriaceae: The exploration of potential Metallo-β-Lactamase inhibitors

2018 ◽  
Author(s):  
Anou M. Somboro ◽  
Daniel G. Amoako ◽  
John Osei Sekyere ◽  
Hezekiel M. Kumalo ◽  
René Khan ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Bacterial Infections ◽  
Clinical Laboratory ◽  
World Health ◽  
Health Concern ◽  
Computational Studies ◽  
Synergistic Activity ◽  
Carbapenem Resistant ◽  
Catalytic Active Site ◽  
Cytotoxicity Effects

AbstractMetallo-β-lactamase producing Enterobacteriaceae are of grave clinical concern particularly as there are no Metallo-β-lactamase (MBL) 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. Minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs), serum effect, fractional inhibitory concentrations index and time-kill kinetics were performed using broth microdilution techniques according to the Clinical Laboratory Standard Institute (CSLI) guidelines. Enzyme kinetic parameters and cytotoxicity 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 to 0.03 mg/L in the presence of TACN. TACN-Meropenem combinations showed bactericidal effects with MIC/MBC ratio of ≤4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be non-cytotoxic 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 = 0.044 µM and inactivation constant kinact= 0.0406 (min-1) demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor.ImportanceCarbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported as 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 carbapenem. This study demonstrated that TACN inhibits MBLs efficiently and holds promises as a potential MBLs inhibitor to help curb the global health threat posed by MBL-producing CREs.

scholarly journals The antimicrobial activity of silver acetate against Acinetobacter baumannii in a Galleria mellonella infection model

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11196
Author(s):  
Eden Mannix-Fisher ◽  
Samantha McLean
Keyword(s):  
Acinetobacter Baumannii ◽  
Bacterial Infections ◽  
Galleria Mellonella ◽  
World Health Organisation ◽  
World Health ◽  
Infection Model ◽  
Silver Acetate ◽  
Selective Toxicity ◽  
Carbapenem Resistant

Background The increasing prevalence of bacterial infections that are resistant to antibiotic treatment has caused the scientific and medical communities to look for alternate remedies aimed at prevention and treatment. In addition to researching novel antimicrobials, there has also been much interest in revisiting some of the earliest therapies used by man. One such antimicrobial is silver; its use stretches back to the ancient Greeks but interest in its medicinal properties has increased in recent years due to the rise in antibiotic resistance. Currently antimicrobial silver is found in everything from lunch boxes to medical device implants. Though much is claimed about the antimicrobial efficacy of silver salts the research in this area is mixed. Methods Herein we investigated the efficacy of silver acetate against a carbapenem resistant strain of Acinetobacter baumannii to determine the in vitro activity of this silver salt against a World Health Organisation designated category I critical pathogen. Furthermore, we use the Galleria mellonella larvae model to assess toxicity of the compound and its efficacy in treating infections in a live host. Results We found that silver acetate can be delivered safely to Galleria at medically relevant and antimicrobial levels without detriment to the larvae and that administration of silver acetate to an infection model significantly improved survival. This demonstrates the selective toxicity of silver acetate for bacterial pathogens but also highlights the need for administration of well-defined doses of the antimicrobial to provide an efficacious treatment.

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.

Drug repurposing for antivirulence therapy against opportunistic bacterial pathogens

2017 ◽  
Vol 1 (1) ◽  
pp. 13-22 ◽  
Author(s):  
Giordano Rampioni ◽  
Paolo Visca ◽  
Livia Leoni ◽  
Francesco Imperi
Keyword(s):  
Bacterial Infections ◽  
Drug Research ◽  
Bacterial Pathogens ◽  
Drug Repurposing ◽  
Health Concern ◽  
Challenges And Opportunities ◽  
New Antibiotics ◽  
Speed Up ◽  
Pathogenic Process

Antibiotic resistance is a serious public health concern at the global level. Available antibiotics have saved millions of lives, but are progressively losing their efficacy against many bacterial pathogens, and very few new antibiotics are being developed by the pharmaceutical industry. Over the last few decades, progress in understanding the pathogenic process of bacterial infections has led researchers to focus on bacterial virulence factors as potential targets for ‘antivirulence' drugs, i.e. compounds which inhibit the ability of bacteria to cause damage to the host, as opposed to inhibition of bacterial growth which is typical of antibiotics. Hundreds of virulence inhibitors have been examined to date in vitro and/or in animal models, but only a few were entered into clinical trials and none were approved, thus hindering the clinical validation of antivirulence therapy. To breathe new life into antivirulence research and speed-up its transfer to the clinic, antivirulence activities have also been sought in drugs already approved for different therapeutic purposes in humans. If effective, these drugs could be repositioned for antivirulence therapy and have an easier and faster transfer to the clinic. In this work we summarize the approaches which have led to the identification of repurposing candidates with antivirulence activities, and discuss the challenges and opportunities related to antivirulence therapy and drug repurposing. While this approach undoubtedly holds promise for boosting antivirulence drug research, some important issues remain to be addressed in order to make antivirulence drugs viable alternatives to traditional antibacterials.

scholarly journals Combination of Colistin and Azidothymidine Demonstrates Synergistic Activity against Colistin-Resistant, Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 8 (12) ◽  
pp. 1964
Author(s):  
Ya-Ting Chang ◽  
Tsung-Ying Yang ◽  
Po-Liang Lu ◽  
Shang-Yi Lin ◽  
Liang-Chun Wang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Therapeutic Option ◽  
Rapid Evolution ◽  
Toxicity Testing ◽  
World Health ◽  
Synergistic Activity ◽  
Carbapenem Resistant

Carbapenem-resistant Enterobacteriaceae (CRE) is listed as an urgent threat by the World Health Organization because of the limited therapeutic options, rapid evolution of resistance mechanisms, and worldwide dissemination. Colistin is a common backbone agent among the “last-resort” antibiotics for CRE; however, its emerging resistance among CRE has taken the present dilemma to the next level. Azidothymidine (AZT), a thymidine analog used to treat human immunodeficiency virus/acquired immunodeficiency syndrome, has been known to possess antibacterial effects against Enterobacteriaceae. In this study, we investigated the combined effects of AZT and colistin in 40 clinical isolates of colistin-resistant, carbapenem-resistant K. pneumoniae (CCRKP). Eleven of the 40 isolates harbored Klebsiella pneumoniae carbapenemase. The in vitro checkerboard method and in vivo nematode killing assay both revealed synergistic activity between the two agents, with fractional inhibitory concentration indexes of ≤0.5 in every strain. Additionally, a significantly lower hazard ratio was observed for the nematodes treated with combination therapy (0.288; p < 0.0001) compared with either AZT or colistin treatment. Toxicity testing indicated potentially low toxicity of the combination therapy. Thus, the AZT–colistin combination could be a potentially favorable therapeutic option for treating CCRKP.

scholarly journals Antibacterial Properties of Organosulfur Compounds of Garlic (Allium sativum)

2021 ◽  
Vol 12 ◽  
Author(s):  
Sushma Bagde Bhatwalkar ◽  
Rajesh Mondal ◽  
Suresh Babu Naidu Krishna ◽  
Jamila Khatoon Adam ◽  
Patrick Govender ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Allium Sativum ◽  
New Technologies ◽  
Antibacterial Properties ◽  
World Health ◽  
Health Concern ◽  
Organosulfur Compounds ◽  
Wide Range ◽  
The World ◽  
Novel Antibiotics

Garlic (Allium sativum), a popular food spice and flavoring agent, has also been used traditionally to treat various ailments especially bacterial infections for centuries in various cultures around the world. The principal phytochemicals that exhibit antibacterial activity are oil-soluble organosulfur compounds that include allicin, ajoenes, and allyl sulfides. The organosulfur compounds of garlic exhibit a range of antibacterial properties such as bactericidal, antibiofilm, antitoxin, and anti-quorum sensing activity against a wide range of bacteria including multi-drug resistant (MDR) strains. The reactive organosulfur compounds form disulfide bonds with free sulfhydryl groups of enzymes and compromise the integrity of the bacterial membrane. The World Health Organization (WHO) has recognized the development of antibiotic resistance as a global health concern and emphasizes antibiotic stewardship along with the urgent need to develop novel antibiotics. Multiple antibacterial effects of organosulfur compounds provide an excellent framework to develop them into novel antibiotics. The review provides a focused and comprehensive portrait of the status of garlic and its compounds as antibacterial agents. In addition, the emerging role of new technologies to harness the potential of garlic as a novel antibacterial agent is discussed.

scholarly journals Preponderance of blaKPC-Carrying Carbapenem-Resistant Enterobacterales Among Fecal Isolates From Community Food Handlers in Kuwait

2021 ◽  
Vol 12 ◽  
Author(s):  
Ola H. Moghnia ◽  
Vincent O. Rotimi ◽  
Noura A. Al-Sweih
Keyword(s):  
Health Concern ◽  
Food Handlers ◽  
Gene Characterization ◽  
E Coli ◽  
Carbapenem Resistant ◽  
Significant Public Health Concern ◽  
The Family ◽  
Significant Public Health ◽  
Molecular Mode ◽  
Sequence Types

Carbapenem-resistant Enterobacterales (CRE) are pathogens that have been found in several countries, with a significant public health concern. Characterizing the mode of resistance and determining the prevailing clones are vital to the epidemiology of CRE in our community. This study was conducted to characterize the molecular mode of resistance and to determine the clonality of the CRE fecal isolates among community food handlers (FHs) vs. infected control patients (ICPs) in Kuwait. Fecal CRE isolates obtained from FHs and ICPs from September 2016 to September 2018 were analyzed for their resistance genes. Gene characterization was carried out by polymerase chain reaction (PCR) assays and sequencing. Clonality of isolates was established by multilocus sequence typing (MLST). Of the 681 and 95 isolates of the family Enterobacterales isolated from FHs and ICPs, 425 (62.4%) and 16 (16.8%) were Escherichia coli, and 18 (2.6%) and 69 (72.6%) were Klebsiella pneumoniae, respectively. A total of 36 isolates were CRE with a prevalence of 5.3% among FH isolates and 87 (91.6%) among the ICPs. Of these, carbapenemase genes were detected in 22 (61.1%) and 65 (74.7%) isolates, respectively (p &lt; 0.05). The detected specific genes among FHs and ICPs were positive for blaKPC 19 (86.4%) and 35 (40.2%), and blaOXA 10 (45.5%) and 59 (67.8%), in addition to blaNDM 2 (9.1%) and 32 (36.8%), respectively. MLST assays of the E. coli and K. pneumoniae isolates revealed considerable genetic diversity and polyclonality as well as demonstrated multiple known ST types and eight novel sequence types. The study revealed a relatively high number of CRE harboring predominantly blaKPC-mediated CRE among the community FH isolates vs. predominant blaOXA genes among the ICPs. Those heterogeneous CRE isolates raise concerns and mandate more efforts toward molecular surveillance. A multinational study is recommended to monitor the spread of genes mediating CRE in the community of Arabian Peninsula countries.

scholarly journals A Synthetic Antibiotic Scaffold Effective Against Multidrug-Resistant Bacterial Pathogens

2021 ◽  
Author(s):  
Matthew Mitcheltree ◽  
Amarnath Pisipati ◽  
Egor A. Syroegin ◽  
Katherine J. Silvestre ◽  
Dorota Klepacki ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Ribosomal Subunit ◽  
Multidrug Resistant ◽  
Health Concern ◽  
Structural Basis ◽  
Resistant Bacteria ◽  
Global Public Health ◽  
Antibiotic Resistant ◽  
New Antibiotics ◽  
Orally Bioavailable

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern. For more than five decades, the search for new antibiotics has relied heavily upon the chemical modification of natural products (semi-synthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semi-synthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, here named iboxamycin. Iboxamycin is effective in strains expressing Erm and Cfr rRNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins, and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native 70S bacterial ribosome, as well as the Erm-methylated 70S ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating bacterial infections, testifying to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.

scholarly journals Inhibitory Activity of β-lactamases by Hydro-Ethanolic Extracts of Harungana madagascariensis, a Plant of the Ivorian Pharmacopoeia

2020 ◽  
pp. 157-162
Author(s):  
Toty Abalé Anatole ◽  
Aka Ayébé Edwige ◽  
Guédé Kipré Bertin ◽  
Konan K. Fernique ◽  
Adrien Jehaes ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Inhibitory Effect ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Water Mixture ◽  
Phytochemical Screening ◽  
Public Health Concern ◽  
Ethanolic Extracts ◽  
New Antibiotics ◽  
Inhibitory Potential

Infection due to multi-resistant bacteria is a public health concern. Unfortunately, the prospect of developing new antibiotics seem not to be on the horizon. Faced with this impasse, medicinal plants could be an alternative for the development of new molecules. The aim of this study was to determine the inhibitory effect of H. madagascariensis extracts on β-lactamases. Extraction of bioactive compounds from trunk barks and leaves of the plant was done in an ethanol-water mixture (70:30). Anti-β-lactamase activity was evaluated by spectrophotometry after the removal of tannins and a phytochemical screening was used to identify the groups of compounds. Concentrations inhibiting 50% of enzyme activity were 0.005±0.001 mg/mL (CTX-M-15), 0.01±0.001 mg/mL (P99) and 0.027±0.009 mg/mL (NDM-1) for bark extracts and 0.704 mg/mL for leaves extracts. Phytochemical screening revealed the presence of flavonoids in bark extracts. The ethanolic extracts of the trunk bark exert a good inhibitory activity on CTX-M-15, P99 and NDM-1 β-lactamases and this activity could be attributed to the presence of the flavonoids. Further studies by bio-guided fractionation of the ethanolic extracts of the bark could yield fractions with high inhibitory potential of β-lactamases.

scholarly journals EXPEDITIOUS RESPONSE TO EPIDEMICS: THE CHRONICLE OF NIPAH IN KERALA

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Rohini Menon ◽  
Rohini Menon ◽  
Rohini Menon ◽  
Rohini Menon ◽  
Rohini Menon ◽  
...  
Keyword(s):  
Nipah Virus ◽  
The State ◽  
World Health ◽  
Health Concern ◽  
Religious Leaders ◽  
Public Health Concern ◽  
Effective Dissemination ◽  
Significant Public Health Concern ◽  
Significant Public Health ◽  
Health Organization

Kerala witnessed a catastrophic outbreak of the Nipah virus (NiV) in May 2018, with a fatality rate of 40-75 per cent. The Nipah virus is recognised by the World Health Organization (WHO) as a significant public health concern, and it's one among the priority diseases for accelerated R&D due to the severe lack of available countermeasures against it. There is no vaccine or cure for the infection. The state of Kerala showed an exemplary response to the outbreak. This involved rapid and effective dissemination of necessary precautions to the broader public. Internet social media played a crucial role in spreading these messages. Although the disease claimed 21 lives, it could have been a lot worse if the state had not taken the measures for proper mitigation. This work gives a brief overview of the Nipah virus, followed by a comprehensive outline of the Kerala outbreak. Community and individual responses to the Nipah outbreak have been analysed to illustrate how various groups and individuals, from health care and tourism departments to religious leaders, played a role in successfully eradicating the virus. Kerala's experience in containing epidemics is expected to become a reference point for other states and regions that may find similar situations.

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