Antibiotic resistance, and, in a broader perspective, antimicrobial resistance (AMR), continues to evolve and spread beyond all boundaries. As a result, infectious diseases have become more ...challenging or even impossible to treat, leading to an increase in morbidity and mortality. Despite the failure of conventional, traditional antimicrobial therapy, in the past two decades, no novel class of antibiotics has been introduced. Consequently, several novel alternative strategies to combat these (multi-) drug-resistant infectious microorganisms have been identified. The purpose of this review is to gather and consider the strategies that are being applied or proposed as potential alternatives to traditional antibiotics. These strategies include combination therapy, techniques that target the enzymes or proteins responsible for antimicrobial resistance, resistant bacteria, drug delivery systems, physicochemical methods, and unconventional techniques, including the CRISPR-Cas system. These alternative strategies may have the potential to change the treatment of multi-drug-resistant pathogens in human clinical settings.
An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current ...level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
The continuing rise in global antimicrobial resistance is seen by many governments and international organizations as a major threat to worldwide health. This means that many publications have ...already described the problems concerning the overuse of currently available antibiotics and potential solutions to this crisis, including the development of new alternatives to antibiotics. However, in this manuscript, the authors approach the subject of increasing global antimicrobial resistance from two perspectives not normally covered by previous publications, namely the ethical use of antibiotics and potential issues relating to the implementation of new antibiotics.
As of 23 April 2021, the outbreak of COVID-19 claimed around 150 million confirmed cases with over 3 million deaths worldwide. Yet, an even more serious but silent pandemic, that of antimicrobial ...resistance (AMR), is likely complicating the outcome of COVID-19 patients. This study discusses the current knowledge on the emergence of the SARS-CoV-2 and highlights the likely contribution of the COVID-19 pandemic on the escalation of AMR. COVID-19 engenders extensive antibiotic overuse and misuse, and will undoubtedly and substantially increase AMR rates worldwide. Amid the expanding COVID-19 pandemic, policymakers should consider the hidden threat of AMR much more, which may well be enhanced through improper use of antibiotics to treat patients with severe COVID-19 infection.
Antimicrobial resistance (AMR) is a natural phenomenon that allows microorganisms to resist to the action of antimicrobial medicines that were previously active against them and cured the infection. AMR is caused by the appropriate and inappropriate use of antimicrobial medicines. The occurrence of the COVID-19 pandemic engenders extensive antimicrobial use that is likely to aggravated the AMR pandemic. This paper discusses the current knowledge on the SARS-CoV-2, and underscores the contribution of the COVID-19 pandemic on the escalation of AMR. Beyond the expanding COVID-19 pandemic, the hidden threat of AMR should also be considered by the decision-makers.
Abstract
The COVID-19 pandemic presents a serious public health challenge in all countries. However, repercussions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on future ...global health are still being investigated, including the pandemic’s potential effect on the emergence and spread of global antimicrobial resistance (AMR). Critically ill COVID-19 patients may develop severe complications, which may predispose patients to infection with nosocomial bacterial and/or fungal pathogens, requiring the extensive use of antibiotics. However, antibiotics may also be inappropriately used in milder cases of COVID-19 infection. Further, concerns such as increased biocide use, antimicrobial stewardship/infection control, AMR awareness, the need for diagnostics (including rapid and point-of-care diagnostics) and the usefulness of vaccination could all be components shaping the influence of the COVID-19 pandemic. In this publication, the authors present a brief overview of the COVID-19 pandemic and associated issues that could influence the pandemic’s effect on global AMR.
The history of antimicrobial resistance (AMR) evolution and the diversity of the environmental resistome indicate that AMR is an ancient natural phenomenon. Acquired resistance is a public health ...concern influenced by the anthropogenic use of antibiotics, leading to the selection of resistant genes. Data show that AMR is spreading globally at different rates, outpacing all efforts to mitigate this crisis. The search for new antibiotic classes is one of the key strategies in the fight against AMR. Since the 1980s, newly marketed antibiotics were either modifications or improvements of known molecules. The World Health Organization (WHO) describes the current pipeline as bleak, and warns about the scarcity of new leads. A quantitative and qualitative analysis of the pre-clinical and clinical pipeline indicates that few antibiotics may reach the market in a few years, predominantly not those that fit the innovative requirements to tackle the challenging spread of AMR. Diversity and innovation are the mainstays to cope with the rapid evolution of AMR. The discovery and development of antibiotics must address resistance to old and novel antibiotics. Here, we review the history and challenges of antibiotics discovery and describe different innovative new leads mechanisms expected to replenish the pipeline, while maintaining a promising possibility to shift the chase and the race between the spread of AMR, preserving antibiotic effectiveness, and meeting innovative leads requirements.
The increasing availability of high-throughput sequencing (frequently termed next-generation sequencing (NGS)) data has created opportunities to gain deeper insights into the mechanisms of a number ...of diseases and is already impacting many areas of medicine and public health. The area of infectious diseases stands somewhat apart from other human diseases insofar as the relevant genomic data comes from the microbes rather than their human hosts. A particular concern about the threat of antimicrobial resistance (AMR) has driven the collection and reporting of large-scale datasets containing information from microbial genomes together with antimicrobial susceptibility test (AST) results. Unfortunately, the lack of clear standards or guiding principles for the reporting of such data is hampering the field's advancement. We therefore present our recommendations for the publication and sharing of genotype and phenotype data on AMR, in the form of 10 simple rules. The adoption of these recommendations will enhance AMR data interoperability and help enable its large-scale analyses using computational biology tools, including mathematical modelling and machine learning. We hope that these rules can shed light on often overlooked but nonetheless very necessary aspects of AMR data sharing and enhance the field's ability to address the problems of understanding AMR mechanisms, tracking their emergence and spread in populations, and predicting microbial susceptibility to antimicrobials for diagnostic purposes.
The increase in antibacterial resistance (ABR) currently equates in the minds of many with the distant fear that certain antibiotics will not work in 30 years on certain bacteria found in places the ...majority of us never go to. However, in reality, rising ABR already seriously threatens the effectiveness of compounds with which we treat common bacterial infections, which means that ABR is currently and will continue to undermine the foundations of modern medicine, including surgery and cancer treatment in hospitals, cities and countries across the world. That is why ABR is widely considered a global threat and one of the biggest problems of our current civilization. Conversely, antibiotic developments to market are few. Therefore, in this paper, we have illustrated the barriers to antimicrobial R&D the following questions and provided solutions to effective antimicrobial R&D.
A flow injection analysis (FIA) system for biochemical assays using time-resolved fluorescence resonance energy transfer (TR-FRET) in the millisecond time scale was developed. As a model system, we ...studied a kinase assay, measuring the phosphorylation of poly(GT)−biotin (substrate) by a receptor tyrosine kinase (epidermal growth factor receptor). A streptavidin labeled with XL665 (SA-XL665)the acceptorwas coupled to the biotin moiety, and an antiphosphotyrosine antibody labeled with europium cryptate (Ab-EuK)the donorwas coupled to the phosphorylated tyrosine group(s). Long-lived FRET can only occur if the substrate is successfully phosphorylated. For the time-resolved detection of such long-lived luminescence phenomena in a flow system, the repetition rate of the excitation source plays a crucial role. Good results were obtained for a small-sized commercially available quadrupled Nd:YAG laser emitting at 266 nm with a repetition rate of 7.8 kHz and a pulse width of 0.3 ns. The long-lived emissions of the donor at 625 nm and that of the acceptor at 665 nm were monitored simultaneously with two photomultipliers, using a delay time of 50 μs and a gate time of 75 μs to exclude background fluorescence interferences. In the FIA experiments, the Ab-EuK concentration was 6 nM and the substrate concentration and SA-XL665 concentrations were 7 nM. By monitoring the intensity changes at 625 and 665 nm, the inhibition of tyrosine kinase by tyrphostin AG1478 was studied and an IC50 value of 5.1 ± 0.4 nM obtained.
A novel approach is presented for studying the chemical interaction between receptor binding sites and ligands. Monohydroxylated polyaromatic compounds were found to be environmentally sensitive ...ligands when applying a special mode of fluorescence: fluorescence line-narrowing spectroscopy (FLNS). With this technique, solvent dependencies and ligand−receptor interactions can be studied in great detail, due to the high spectral resolution and the fact that at cryogenic temperatures (4 K), no solvent reorientation effects complicate the interpretation. The FLN spectrum of a ligand bound to the receptor is compared to the spectra of the free ligand in solvent mixtures that mimic the functionalities present within the receptor's binding site. It is shown that for the well-known estrogen receptor (ER), the orientations of two xenoestrogenic ligands 3- and 9-hydroxybenzoapyrene (3- and 9-OH-BaP) can be determined. The FLN results clearly indicate that an H-bond accepted by HIS524 plays a major role in the binding of these ligands to the ER. Furthermore, the spectra indicated a π−π stacking aromatic interaction for 9-OH-BaP with PHE404. These results are in line with molecular modeling studies published earlier.
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