Enzyme Inhibitors: The Best Strategy to Tackle Superbug NDM-1 and Its Variants

Multidrug bacterial resistance endangers clinically effective antimicrobial therapy and continues to cause major public health problems, which have been upgraded to unprecedented levels in recent years, worldwide. β-Lactam antibiotics have become an important weapon to fight against pathogen infections due to their broad spectrum. Unfortunately, the emergence of antibiotic resistance genes (ARGs) has severely astricted the application of β-lactam antibiotics. Of these, New Delhi metallo-β-lactamase-1 (NDM-1) represents the most disturbing development due to its substrate promiscuity, the appearance of variants, and transferability. Given the clinical correlation of β-lactam antibiotics and NDM-1-mediated resistance, the discovery, and development of combination drugs, including NDM-1 inhibitors, for NDM-1 bacterial infections, seems particularly attractive and urgent. This review summarizes the research related to the development and optimization of effective NDM-1 inhibitors. The detailed generalization of crystal structure, enzyme activity center and catalytic mechanism, variants and global distribution, mechanism of action of existing inhibitors, and the development of scaffolds provides a reference for finding potential clinically effective NDM-1 inhibitors against drug-resistant bacteria.

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New Delhi metallo-beta-lactamase-1: A weapon for the newly emerging drug-resistant bacteria

Indian Journal of Medical Sciences ◽

10.18203/issn.0019-5359.indianjmedsci20170487 ◽

2017 ◽

Vol 69 (1) ◽

pp. 29

Author(s):

Sanghamitra Padhi

Keyword(s):

Bacterial Infections ◽

Medical Literature ◽

Resistant Bacteria ◽

New Delhi ◽

Beta Lactamase ◽

Drug Resistant ◽

Recent Past ◽

Bacterial Strains ◽

Drug Resistant Bacteria ◽

Micro Organisms

The world has seen the emergence of many micro-organisms in the recent past which can curb the human population with their newly built genetic make-up. The latest addition to this list of panic creating organisms is, bacteria encoding the gene for New Delhi metallo-beta-lactamase (NDM)-1. NDM-1 is an enzyme that can hydrolyse and inactivate carbapenems, which are used as a last resort for the treatment of multiresistant bacterial infections. Name of these bacteria were not found in the medical literature before December 2009, because of which it can take the credit of becoming a powerful emerging bacteria which are difficult to treat. Besides Escherichia coli and Klebsiella pneumoniae, other bacterial strains have also expressed the gene for NDM-1, which are detected in many countries.<div> </div>

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MATHEMATICAL MODELING OF BACTERIAL RESISTANCE TO ANTIBIOTICS BY MUTATIONS AND PLASMIDS

Journal of Biological System ◽

10.1142/s0218339016500078 ◽

2016 ◽

Vol 24 (01) ◽

pp. 129-146 ◽

Cited By ~ 6

Author(s):

EDUARDO IBARGÜEN-MONDRAGÓN ◽

JHOANA P. ROMERO-LEITON ◽

LOURDES ESTEVA ◽

EDITH MARIELA BURBANO-ROSERO

Keyword(s):

Mathematical Modeling ◽

Bacterial Infections ◽

Bacterial Resistance ◽

Temporal Dynamics ◽

Deterministic Model ◽

Transmission Model ◽

Resistant Bacteria ◽

Drug Resistant ◽

Development Of Resistance ◽

Drug Resistant Bacteria

Diversity of drugs against bacterial infections, and development of resistance to such drugs are increasing. We formulate and analyze a deterministic model for the population dynamics of sensitive and resistant bacteria to multiple bactericidal and bacteriostatic antibiotics, assuming that drug resistance is acquired through mutations and plasmid transmission. Model equilibria are determined from qualitative analysis, and numerical simulations are used to assess temporal dynamics of sensitive and drug-resistant bacteria. The model presents three possibilities: elimination of bacteria, persistence of only resistant bacteria, or coexistence of sensitive and resistant bacteria. Evolution to one of these scenarios depends on thresholds numbers involving sensitive and resistant bacteria.

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Re-challenging antibiotic resistance with Daniel Berman

Video Journal of Biomedicine ◽

10.2217/vjbm-2020-0006 ◽

2020 ◽

Author(s):

Daniel Berman

Keyword(s):

Bacterial Infections ◽

Point Of Care ◽

Healthcare Setting ◽

Rapid Diagnostic Tests ◽

Resistant Bacteria ◽

Drug Resistant ◽

Drug Resistant Bacteria ◽

Global Threat ◽

The Right ◽

Point Of Care Tests

How can we prevent the rise of resistance to antibiotics? In this video, Daniel Berman, Nesta Challenges, discusses the global threat of AMR and how prizes like the Longitude Prize can foster the development of rapid diagnostic tests for bacterial infections, helping to contribute towards reducing the global threat of drug resistant bacteria. Daniel outlines how accelerating the development of rapid point-of-care tests will ensure that bacterial infections are treated with the most appropriate antibiotic, at the right time and in the right healthcare setting.

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Tackling Virulence of Pseudomonas aeruginosa by the Natural Furanone Sotolon

Antibiotics ◽

10.3390/antibiotics10070871 ◽

2021 ◽

Vol 10 (7) ◽

pp. 871

Author(s):

Mohammed F. Aldawsari ◽

El-Sayed Khafagy ◽

Ahmed Al Saqr ◽

Ahmed Alalaiwe ◽

Hisham A. Abbas ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Virulence Factors ◽

Bacterial Infections ◽

Therapeutic Agent ◽

Bacterial Resistance ◽

Inhibitory Concentration ◽

Bacterial Biofilm ◽

Resistant Bacteria ◽

Resistance Development

The bacterial resistance development due to the incessant administration of antibiotics has led to difficulty in their treatment. Natural adjuvant compounds can be co-administered to hinder the pathogenesis of resistant bacteria. Sotolon is the prevailing aromatic compound that gives fenugreek its typical smell. In the current work, the anti-virulence activities of sotolon on Pseudomonas aeruginosa have been evaluated. P. aeruginosa has been treated with sotolon at sub-minimum inhibitory concentration (MIC), and production of biofilm and other virulence factors were assessed. Moreover, the anti-quorum sensing (QS) activity of sotolon was in-silico evaluated by evaluating the affinity of sotolon to bind to QS receptors, and the expression of QS genes was measured in the presence of sotolon sub-MIC. Furthermore, the sotolon in-vivo capability to protect mice against P. aeruginosa was assessed. Significantly, sotolon decreased the production of bacterial biofilm and virulence factors, the expression of QS genes, and protected mice from P. aeruginosa. Conclusively, the plant natural substance sotolon attenuated the pathogenicity of P. aeruginosa, locating it as a plausible potential therapeutic agent for the treatment of its infections. Sotolon can be used in the treatment of bacterial infections as an alternative or adjuvant to antibiotics to combat their high resistance to antibiotics.

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Environmental Spread of New Delhi Metallo-β-Lactamase-1-Producing Multidrug-Resistant Bacteria in Dhaka, Bangladesh

Applied and Environmental Microbiology ◽

10.1128/aem.00793-17 ◽

2017 ◽

Vol 83 (15) ◽

Cited By ~ 32

Author(s):

Mohammad Aminul Islam ◽

Moydul Islam ◽

Rashedul Hasan ◽

M. Iqbal Hossain ◽

Ashikun Nabi ◽

...

Keyword(s):

Antibiotic Resistance ◽

Resistance Genes ◽

Tap Water ◽

Antibiotic Resistance Genes ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

New Delhi ◽

Multidrug Resistant Bacteria ◽

Content Type ◽

Wastewater Samples

ABSTRACT Resistance to carbapenem antibiotics through the production of New Delhi metallo-β-lactamase-1 (NDM-1) constitutes an emerging challenge in the treatment of bacterial infections. To monitor the possible source of the spread of these organisms in Dhaka, Bangladesh, we conducted a comparative analysis of wastewater samples from hospital-adjacent areas (HAR) and from community areas (COM), as well as public tap water samples, for the occurrence and characteristics of NDM-1-producing bacteria. Of 72 HAR samples tested, 51 (71%) samples were positive for NDM-1-producing bacteria, as evidenced by phenotypic tests and the presence of the bla NDM-1 gene, compared to 5 of 41 (12.1%) samples from COM samples (P < 0.001). All tap water samples were negative for NDM-1-producing bacteria. Klebsiella pneumoniae (44%) was the predominant bacterial species among bla NDM-1-positive isolates, followed by Escherichia coli (29%), Acinetobacter spp. (15%), and Enterobacter spp. (9%). These bacteria were also positive for one or more other antibiotic resistance genes, including bla CTX-M-1 (80%), bla CTX-M-15 (63%), bla TEM (76%), bla SHV (33%), bla CMY-2 (16%), bla OXA-48-like (2%), bla OXA-1 (53%), and bla OXA-47-like (60%) genes. Around 40% of the isolates contained a qnr gene, while 50% had 16S rRNA methylase genes. The majority of isolates hosted multiple plasmids, and plasmids of 30 to 50 MDa carrying bla NDM-1 were self-transmissible. Our results highlight a number of issues related to the characteristics and source of spread of multidrug-resistant bacteria as a potential public health threat. In view of the existing practice of discharging untreated liquid waste into the environment, hospitals in Dhaka city contribute to the potential dissemination of NDM-1-producing bacteria into the community. IMPORTANCE Infections caused by carbapenemase-producing Enterobacteriaceae are extremely difficult to manage due to their marked resistance to a wide range of antibiotics. NDM-1 is the most recently described carbapenemase, and the bla NDM-1 gene, which encodes NDM-1, is located on self-transmissible plasmids that also carry a considerable number of other antibiotic resistance genes. The present study shows a high prevalence of NDM-1-producing organisms in the wastewater samples from hospital-adjacent areas as a potential source for the spread of these organisms to community areas in Dhaka, Bangladesh. The study also examines the characteristics of the isolates and their potential to horizontally transmit the resistance determinants. The significance of our research is in identifying the mode of spread of multiple-antibiotic-resistant organisms, which will allow the development of containment measures, leading to broader impacts in reducing their spread to the community.

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Recent advances: peptides and self-assembled peptide-nanosystems for antimicrobial therapy and diagnosis

Biomaterials Science ◽

10.1039/d0bm00789g ◽

2020 ◽

Vol 8 (18) ◽

pp. 4975-4996

Author(s):

Pengfei Zou ◽

Wen-Ting Chen ◽

Tongyi Sun ◽

Yuanyuan Gao ◽

Li-Li Li ◽

...

Keyword(s):

Human Health ◽

Antimicrobial Therapy ◽

Bacterial Infections ◽

The Body ◽

Resistant Bacteria ◽

Drug Resistant ◽

Self Assembling ◽

Recent Advances ◽

Drug Resistant Bacteria ◽

Therapy And Diagnosis

Bacterial infections, especially the refractory treatment of drug-resistant bacteria, are one of the greatest threats to human health. Self-assembling peptide-based strategies can specifically detect the bacteria at the site of infection in the body and kill it.

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Antibiotics in Food Chain: The Consequences for Antibiotic Resistance

Antibiotics ◽

10.3390/antibiotics9100688 ◽

2020 ◽

Vol 9 (10) ◽

pp. 688

Author(s):

Shashi B. Kumar ◽

Shanvanth R. Arnipalli ◽

Ouliana Ziouzenkova

Keyword(s):

Public Health ◽

Antibiotic Resistance ◽

Food Chain ◽

Bacterial Infections ◽

Antibiotic Resistance Genes ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Alternative Strategies ◽

Antibiotic Resistant ◽

Continuous Use

Antibiotics have been used as essential therapeutics for nearly 100 years and, increasingly, as a preventive agent in the agricultural and animal industry. Continuous use and misuse of antibiotics have provoked the development of antibiotic resistant bacteria that progressively increased mortality from multidrug-resistant bacterial infections, thereby posing a tremendous threat to public health. The goal of our review is to advance the understanding of mechanisms of dissemination and the development of antibiotic resistance genes in the context of nutrition and related clinical, agricultural, veterinary, and environmental settings. We conclude with an overview of alternative strategies, including probiotics, essential oils, vaccines, and antibodies, as primary or adjunct preventive antimicrobial measures or therapies against multidrug-resistant bacterial infections. The solution for antibiotic resistance will require comprehensive and incessant efforts of policymakers in agriculture along with the development of alternative therapeutics by experts in diverse fields of microbiology, biochemistry, clinical research, genetic, and computational engineering.

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Antibacterial Prodrugs to Overcome Bacterial Resistance

Molecules ◽

10.3390/molecules25071543 ◽

2020 ◽

Vol 25 (7) ◽

pp. 1543 ◽

Cited By ~ 3

Author(s):

Buthaina Jubeh ◽

Zeinab Breijyeh ◽

Rafik Karaman

Keyword(s):

Bacterial Resistance ◽

Active Drug ◽

Resistant Bacteria ◽

Drug Resistant ◽

Pharmacological Effects ◽

New Drug ◽

Drug Resistant Bacteria ◽

Drug Treatments ◽

New Treatments ◽

Novel Antibiotics

Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria.

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Bacteriophage Therapy of Chronic Nonhealing Wound: Clinical Study

The International Journal of Lower Extremity Wounds ◽

10.1177/1534734619835115 ◽

2019 ◽

Vol 18 (2) ◽

pp. 171-175 ◽

Cited By ~ 14

Author(s):

Pooja Gupta ◽

Hari Shankar Singh ◽

Vijay K. Shukla ◽

Gopal Nath ◽

Satyanam Kumar Bhartiya

Keyword(s):

Wound Healing ◽

Biofilm Formation ◽

Bacterial Infections ◽

Chronic Wounds ◽

Bacterial Count ◽

Complete Healing ◽

Resistant Bacteria ◽

Bacteriophage Therapy ◽

Inflammatory Phase ◽

Drug Resistant Bacteria

Background: A chronic wound usually results due to halt in the inflammatory phase of wound healing. Bacterial infections and biofilm formation are considered to be the basic cause of it. Chronic wounds significantly impair the quality of life. Antibiotics are now failing due to biofilm formation emergence of drug-resistant bacteria. Objective: This study aims to see the effect of bacteriophage therapy in chronic nonhealing wound infected with the following bacteria: Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Subject: Patients with chronic nonhealing wound not responding to conventional local debridement and antibiotic therapy were included in the study. The age of patients ranged between 12 and 60 years. Method: A total of 20 patients selected and tissue biopsies and wound swabs were taken for isolation of the bacteria. After confirmation of organism, a cocktail of customized bacteriophages was topically applied over the wound on alternate days till the wound surface became microbiologically sterile. Mean bacterial count and clinical assessment were done and compared at the time of presentation and after 3 and 5 doses of application. Results: A significant improvement was observed in the wound healing, and there were no signs of infection clinically and microbiologically after 3 to 5 doses of topical bacteriophage therapy. Seven patients achieved complete healing on day21 during follow up while in others healthy margins and healthy granulation tissue were observed. Conclusion: Topical bacteriophage application may be quite effective therapy for the treatment of chronic nonhealing wounds.

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Dual functional β-peptide polymer-modified resin beads for bacterial killing and endotoxin adsorption

BMC Materials ◽

10.1186/s42833-019-0005-3 ◽

2019 ◽

Vol 1 (1) ◽

Cited By ~ 13

Author(s):

Yuxin Qian ◽

Yue Shen ◽

Shuai Deng ◽

Tingyan Liu ◽

Fan Qi ◽

...

Keyword(s):

Bacterial Infections ◽

Bacterial Resistance ◽

Resistant Bacteria ◽

High Concentration ◽

Major Step ◽

Bacterial Killing ◽

Host Defense Peptides ◽

Dual Functional ◽

Resin Beads ◽

Bacteria Killing

Abstract Background Bacterial infections and endotoxin contaminations are serious problems in the production/manufacture of food, water, drinks, and injections. The development of effective materials to kill bacteria and adsorb endotoxins, particularly those caused by gram-negative bacteria, represents a major step toward improved safety. As synthetic mimic of host defense peptides, β-peptide polymers are not susceptible to bacterial resistance and exhibit potent bacteria-killing abilities upon antibiotic-resistant bacteria. This study investigated the potential of synthetic β-peptide polymer-modified polyacrylate (PA) beads to kill bacteria and remove endotoxin, i.e. lipopolysaccharide (LPS), produced by these bacteria. Results Synthetic β-peptide polymer-modified PA beads displayed strong antimicrobial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus, as well as excellent biocompatibility. In addition, these β-peptide polymer-modified beads removed around 90% of the endotoxins, even at 200 EU/mL of LPS, a very high concentration of LPS. Conclusions β-peptide polymer-modified PA beads are efficient in bacterial killing and endotoxin adsorption. Hence, these modified beads demonstrate the potential application in the production/manufacture of food, water, drinks, and injections.

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