scholarly journals The Concept of an Ideal Antibiotic: Implications for Drug Design

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 892 ◽  
Author(s):  
Márió Gajdács
Keyword(s):  
Multidrug Resistant ◽  
Public Health Issue ◽  
Pharmaceutical Companies ◽  
Antibacterial Drug ◽  
Financial Risks ◽  
Antibiotic Resistant ◽  
Chemical Structures ◽  
Antibiotic Drug ◽  
Global Action ◽  
New Antibiotics

The emergence and spread of antibiotic-resistant pathogens is a major public health issue, which requires global action of an intersectoral nature. Multidrug-resistant (MDR) pathogens—especially “ESKAPE” bacteria—can withstand lethal doses of antibiotics with various chemical structures and mechanisms of action. Pharmaceutical companies are increasingly turning away from participating in the development of new antibiotics, due to the regulatory environment and the financial risks. There is an urgent need for innovation in antibiotic research, as classical discovery platforms (e.g., mining soil Streptomycetes) are no longer viable options. In addition to discovery platforms, a concept of an ideal antibiotic should be postulated, to act as a blueprint for future drugs, and to aid researchers, pharmaceutical companies, and relevant stakeholders in selecting lead compounds. Based on 150 references, the aim of this review is to summarize current advances regarding the challenges of antibiotic drug discovery and the specific attributes of an ideal antibacterial drug (a prodrug or generally reactive compound with no specific target, broad-spectrum antibacterial activity, adequate penetration through the Gram-negative cell wall, activity in biofilms and in hard-to-treat infections, accumulation in macrophages, availability for oral administration, and for use in sensitive patient groups).

scholarly journals Multidrug-Resistant Bacteria Isolated from Different Aquatic Environments in the North of Spain and South of France

2020 ◽  
Vol 8 (9) ◽  
pp. 1425
Author(s):  
Lara Pérez-Etayo ◽  
David González ◽  
José Leiva ◽  
Ana Isabel Vitas
Keyword(s):  
Wastewater Treatment Plants ◽  
Multidrug Resistant ◽  
World Health ◽  
Resistant Bacteria ◽  
Aquatic Environments ◽  
Multidrug Resistant Bacteria ◽  
Antibiotic Resistant ◽  
The North ◽  
New Antibiotics ◽  
Health Organization

Due to the global progress of antimicrobial resistance, the World Health Organization (WHO) published the list of the antibiotic-resistant “priority pathogens” in order to promote research and development of new antibiotics to the families of bacteria that cause severe and often deadly infections. In the framework of the One Health approach, the surveillance of these pathogens in different environments should be implemented in order to analyze their spread and the potential risk of transmission of antibiotic resistances by food and water. Therefore, the objective of this work was to determine the presence of high and critical priority pathogens included in the aforementioned list in different aquatic environments in the POCTEFA area (North Spain–South France). In addition to these pathogens, detection of colistin-resistant Enterobacteriaceae was included due its relevance as being the antibiotic of choice to treat infections caused by multidrug resistant bacteria (MDR). From the total of 80 analyzed samples, 100% of the wastewater treatment plants (WWTPs) and collectors (from hospitals and slaughterhouses) and 96.4% of the rivers, carried antibiotic resistant bacteria (ARB) against the tested antibiotics. Fifty-five (17.7%) of the isolates were identified as target microorganisms (high and critical priority pathogens of WHO list) and 58.2% (n = 32) of them came from WWTPs and collectors. Phenotypic and genotypic characterization showed that 96.4% were MDR and resistance to penicillins/cephalosporins was the most widespread. The presence of bla genes, KPC-type carbapenemases, mcr-1 and vanB genes has been confirmed. In summary, the presence of clinically relevant MDR bacteria in the studied aquatic environments demonstrates the need to improve surveillance and treatments of wastewaters from slaughterhouses, hospitals and WWTPs, in order to minimize the dispersion of resistance through the effluents of these areas.

Something old, something new: revisiting natural products in antibiotic drug discovery

2014 ◽  
Vol 60 (3) ◽  
pp. 147-154 ◽  
Author(s):  
Gerard D. Wright
Keyword(s):  
Natural Products ◽  
New Drugs ◽  
Clinical Use ◽  
Antibiotic Resistant ◽  
Antibiotic Drug ◽  
New Antibiotics ◽  
Bacteria And Fungi ◽  
Antibiotic Discovery ◽  
Novel Drug ◽  
New Strategies

Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an “apocalyptic” threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.

scholarly journals Fosfomycin

2016 ◽  
Vol 29 (2) ◽  
pp. 321-347 ◽  
Author(s):  
Matthew E. Falagas ◽  
Evridiki K. Vouloumanou ◽  
George Samonis ◽  
Konstantinos Z. Vardakas
Keyword(s):  
Bacterial Infections ◽  
Clinical Effectiveness ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Antibiotic Resistant ◽  
Development Of Resistance ◽  
Extensively Drug Resistant ◽  
New Antibiotics

SUMMARYThe treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, thein vitroactivity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.

scholarly journals Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Adam D. Tomich ◽  
Erik H. Klontz ◽  
Daniel Deredge ◽  
John P. Barnard ◽  
Christi L. McElheny ◽  
...  
Keyword(s):  
Small Molecule ◽  
Multidrug Resistant ◽  
Public Health Issue ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Track Record ◽  
New Strategy ◽  
New Antibiotics ◽  
Resistant Strains

ABSTRACTThe spread of multidrug or extensively drug-resistant Gram-negative bacteria is a serious public health issue. There are too few new antibiotics in development to combat the threat of multidrug-resistant infections, and consequently the rate of increasing antibiotic resistance is outpacing the drug development process. This fundamentally threatens our ability to treat common infectious diseases. Fosfomycin (FOM) has an established track record of safety in humans and is highly active againstEscherichia coli, including multidrug-resistant strains. However, many other Gram-negative pathogens, including the “priority pathogens”Klebsiella pneumoniaeandPseudomonas aeruginosa, are inherently resistant to FOM due to the chromosomalfosAgene, which directs expression of a metal-dependent glutathioneS-transferase (FosA) that metabolizes FOM. In this study, we describe the discovery and biochemical and structural characterization of ANY1 (3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one), a small-molecule active-site inhibitor of FosA. Importantly, ANY1 potentiates FOM activity in representative Gram-negative pathogens. Collectively, our study outlines a new strategy to expand FOM activity to a broader spectrum of Gram-negative pathogens, including multidrug-resistant strains.

scholarly journals Reinventing the antimicrobial pipeline in response to the global crisis of antimicrobial-resistant infections

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 238 ◽  
Author(s):  
Andrew C. Singer ◽  
Claas Kirchhelle ◽  
Adam P. Roberts
Keyword(s):  
Antimicrobial Resistance ◽  
Open Science ◽  
Resistant Bacteria ◽  
Pharmaceutical Companies ◽  
Economic Return ◽  
Antibiotic Resistant ◽  
Proposed Model ◽  
New Antibiotics ◽  
Permanent Staff

The pipeline for new antibiotics is dry. Despite the creation of public/private initiatives like Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (Carb-X) and the Antimicrobial Resistance (AMR) Centre, the current focus on ‘push-pull’ incentives for the pharmaceutical industry still relies on economic return. We propose a joint, internationally-funded antimicrobial development institute that would fund permanent staff to take on roles previously assigned to pharmaceutical companies. This institute would receive ring-fenced, long-term, core funding from participating countries as well as charities, with the aim to focus on transforming the largely dormant antimicrobial pipeline. Resulting drugs would be sold globally and according to a principle of shared burdens. Our proposed model for antimicrobial development aims to maximise society’s investment, through open science, investment in people, and the sharing of intellectual property.

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 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 In Vitro Evaluation of Antimicrobial Activity and Cytotoxicity of Different Nanobiotics Targeting Multidrug Resistant and Biofilm Forming Staphylococci

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Mennatallah A. Mohamed ◽  
Maha Nasr ◽  
Walid F. Elkhatib ◽  
Wafaa N. Eltayeb
Keyword(s):  
Antimicrobial Activity ◽  
Rat Hepatocytes ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Antibiotic Resistant ◽  
Diphenyltetrazolium Bromide ◽  
New Antibiotics ◽  
Conventional Antibiotics

Antibiotic-resistant and biofilm-forming bacteria have surprisingly increased over recent years. On the contrary, the rate of development of new antibiotics to treat these emerging superbugs is very slow. Therefore, the aim of this study was to prepare novel nanobiotic formulations to improve the antimicrobial activity of three antibiotics (linezolid, doxycycline, and clindamycin) against Staphylococci. Antibiotics were formulated as nanoemulsions and evaluated for their antimicrobial activities and cytotoxicities. Cytotoxicity of the conventional antibiotics and nanobiotics was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on rat hepatocytes. Half-maximal inhibitory concentration (IC50) was estimated from an experimentally derived dose-response curve for each concentration using GraphPad Prism software. Upon quantitative assessment of Staphylococcus biofilm formation, eighty-four isolates (66.14 %) were biofilm forming. Linezolid and doxycycline nanobiotics exhibited promising antibacterial activities. On the contrary, clindamycin nanobiotic exhibited poor antibacterial activity. Minimum biofilm inhibitory concentrations showed that 73.68 %, 45.6%, and 5.2% of isolates were sensitive to linezolid, doxycycline, and clindamycin nanobiotics, respectively. Results of this study revealed that antibiotics loaded in nanosystems had a higher antimicrobial activity and lower cytotoxicities as compared to those of conventional free antibiotics, indicating their potential therapeutic values.

scholarly journals Multicenter Study of the Burden of Multidrug-Resistant Bacteria in the Etiology of Infected Diabetic Foot Ulcers

2019 ◽  
Author(s):  
Adeyemi Temitayo Adeyemo ◽  
Babatope A. Kolawole ◽  
Vincent Olubunmi Rotimi ◽  
Aaron Oladipo Aboderin
Keyword(s):  
Diabetic Foot ◽  
Anaerobic Bacteria ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Aerobic Bacteria ◽  
Public Health Issue ◽  
Resistant Bacteria ◽  
Published Data ◽  
Antibacterial Drug ◽  
Etiological Agents

AbstractBackgroundInfected diabetic foot ulcer (IDFU) is a public health issue and a leading cause of non-traumatic limb amputation. Very few published data on IDFU is available in most West African countries. The objective of this study was to investigate the etiological agents of IDFU and the challenge of antibacterial drug resistance in the management of infections.MethodsThis was a prospective cross-sectional hospital-based study involving three tertiary healthcare facilities. Consecutive eligible patients presenting in the facilities were recruited. Tissue biopsies and/or aspirates were collected and cultured on a set of selective and non-selective media and incubated in appropriate atmospheric conditions for 24 to 72 hours. Isolates were identified by established standard methods. Antibiotic susceptibility testing was performed using modified Kirby-Bauer disc diffusion method. Specific resistance determinants were investigated by polymerase chain reaction-based protocols. Data analysis was done with SPSS version 20.ResultsNinety patients with clinical diagnosis of DFI were studied between July 2016 and April 2017. A total of 218 microorganisms were isolated, comprising 129 (59.2%) Gram-negative bacilli (GNB), 59 (27.1%) Gram-positive cocci (GPC) and 29 (13.2%) anaerobic bacteria. The top five facultative/aerobic bacteria encountered were: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Citrobacter spp. representing 41 (18.8%), 23 (10.5%), 20 (9.2%), 19 (8.7%) and 19 (8.7%) isolates, in that order, respectively. The commonest anaerobes were Bacteroides spp., and Peptostreptococcus anaerobius which accounted for 7 (24.1%) and 6 (20.7%), respectively. Of the 93 IDFU cases, 74 (80%) were infected by multidrug-resistant (MDR) bacteria predominantly methicillin-resistant S. aureus, extended-spectrum β-lactamase-producing GNB, mainly of the CTX-M variety. Only 4 (3.1%) GNB were carbapenemase-producers encoded by blaVIM. Factors associated with presence of MDR bacteria were peripheral neuropathy (r= 4.05, P= 0.042) and duration of foot infection >1 month(r= 7.63, P= 0.015).ConclusionsMDR facultative/aerobic bacteria are overrepresented amongst agents causing IDFU. A relatively low proportion of the etiological agents were anaerobic bacteria. This finding should help formulate empirical therapeutic options for managing IDFU. Furthermore, drastic reduction in inappropriate use of cocktail of antibiotics for IDFUs is advocated to combat infection by MDR bacteria in these patients.

The international and national challenges faced in ensuring prudent use of antibiotics

2016 ◽  
Author(s):  
Susan Hopkins
Keyword(s):  
World Health ◽  
Public Health Issue ◽  
Resistant Bacteria ◽  
Healthcare Organizations ◽  
Antibiotic Resistant ◽  
The Public ◽  
The World ◽  
New Antibiotics ◽  
Minor Injuries ◽  
Health Organization

In April 2014, the World Health Organization reinforced that without urgent coordinated action by most stakeholders the world is headed for a post-antibiotic era in which common infections and minor injuries, which have been treatable for decades, could kill once again. With the rise in the number of infections due to antibiotic-resistant bacteria and the lack of development of new antibiotics, antimicrobial resistance is a major clinical and public health issue that society needs to tackle. This chapter focuses on the challenges of drug resistance and antimicrobial development together with how healthcare organizations can address this threat. A number of initiatives are discussed, including how prescribers and the public need to ensure that antimicrobials are used widely to prevent any collateral damage.

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