Fighting against evolution of antibiotic resistance by utilizing evolvable antimicrobial drugs. - Related Documents




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81301.0000Fighting against evolution of antibiotic resistance by utilizing evolvable antimicrobial drugs. Antibiotic resistance is a worldwide public health problem (Bush et al. in Nat Rev Microbiol 9:894-896, 2011). The lack of effective therapies against resistant bacteria globally leads to prolonged treatments, increased mortality, and inflating health care costs (Oz et al. in Mol Biol Evol 31:2387-2401, 2014; Martinez in Science 321:365-367, 2008; Lipsitch et al. in Proc Natl Acad Sci USA 97:1938-1943, 2000; Taubes in Science 321:356-361, 2008; Laxminarayan et al. in Lancet, 2016; Laxminarayan et al. in Lancet Infect Dis 13:1057-1098, 2013). Current efforts towards a solution of this problem can be boiled down to two main strategies: (1) developing of new antimicrobial agents and (2) searching for smart strategies that can restore or preserve the efficacy of existing antimicrobial agents. In this short review article, we discuss the need for evolvable antimicrobial agents, focusing on a new antimicrobial technology that utilizes peptide-conjugated phosphorodiamidate morpholino oligomers to inhibit the growth of pathogenic bacteria by targeting bacterial genes.201728497241
905810.9951Antisense Agents against Antibiotic-resistant Bacteria. The dramatically increasing levels of antibiotic resistance are being seen worldwide and are a significant threat to public health. Antibiotic and drug resistance is seen in various bacterial species. Antibiotic resistance is associated with increased morbidity and mortality and increased treatment costs. Antisense-related technologies include oligonucleotides that interfere with gene transcription and expression; these oligonucleotides can help treat antibiotic-resistant bacteria. The important oligonucleotides include Peptide Nucleic Acids (PNAs), Phosphorodiamidate Morpholino Oligomers (PPMOs), and Locked Nucleic Acids (LNAs). Typically, the size of these structures (oligonucleotides) is 10 to 20 bases. PNAs, PPMOs, and LNAs are highlighted in this review as targets for genes that cause the gene to be destroyed and impede bacterial growth. These results open a new perspective for therapeutic intervention. Future studies need to examine different aspects of antisense agents, such as the safety, toxicity, and pharmacokinetic properties of antisense agents in clinical treatment.202235034590
999820.9948mSphere of Influence: Uncovering New Ways To Control Multidrug Resistance by Dissecting Essential Cell Processes. Ana L. Flores-Mireles works in the fields of microbial pathogenesis and development of new therapeutics. In this mSphere of Influence article, she reflects on how the papers "Bacterial cell wall biogenesis is mediated by SEDS and PBP polymerase families functioning semi-autonomously" by H. Cho et al. (Nat Microbiol 1:16172, 2016, https://doi.org/10.1038/nmicrobiol.2016.172) and "A comprehensive, CRISPR-based functional analysis of essential genes in bacteria" by J. M. Peters et al. (Cell 165:1493-1506, 2016, https://doi.org/10.1016/j.cell.2016.05.003) made an impact on her approach to dissecting essential processes to understand microbial pathogenesis in catheter-associated urinary tract infections and generate an effective treatment with reduced likelihood of developing resistance.201931554727
952430.9946The Role of Nitroreductases in Resistance to Nitroimidazoles. Antimicrobial resistance is a major challenge facing modern medicine, with an estimated 700,000 people dying annually and a global cost in excess of $100 trillion. This has led to an increased need to develop new, effective treatments. This review focuses on nitroimidazoles, which have seen a resurgence in interest due to their broad spectrum of activity against anaerobic Gram-negative and Gram-positive bacteria. The role of nitroreductases is to activate the antimicrobial by reducing the nitro group. A decrease in the activity of nitroreductases is associated with resistance. This review will discuss the resistance mechanisms of different disease organisms, including Mycobacterium tuberculosis, Helicobacter pylori and Staphylococcus aureus, and how these impact the effectiveness of specific nitroimidazoles. Perspectives in the field of nitroimidazole drug development are also summarised.202134062712
974640.9946Fluoroamphiphilic polymers exterminate multidrug-resistant Gram-negative ESKAPE pathogens while attenuating drug resistance. ESKAPE pathogens are a panel of most recalcitrant bacteria that could "escape" the treatment of antibiotics and exhibit high incidence of drug resistance. The emergence of multidrug-resistant (MDR) ESKAPE pathogens (particularly Gram-negative bacteria) accounts for high risk of mortality and increased resource utilization in health care. Worse still, there has been no new class of antibiotics approved for exterminating the Gram-negative bacteria for more than 50 years. Therefore, it is urgent to develop novel antibacterial agents with low resistance and potent killing efficacy against Gram-negative ESKAPE pathogens. Herein, we present a class of fluoropolymers by mimicking the amphiphilicity of cationic antimicrobial peptides. Our optimal fluoroamphiphilic polymer (PD(45)HF(5)) displayed selective antimicrobial ability for all MDR Gram-negative ESAKPE pathogens, low resistance, high in vitro cell selectivity, and in vivo curative efficacy. These findings implied great potential of fluoroamphiphilic cationic polymers as promising antibacterial agents against MDR Gram-negative ESKAPE bacteria and alleviating antibiotic resistance.202439196947
474850.9946Bacteria antibiotic resistance: New challenges and opportunities for implant-associated orthopedic infections. There has been a dramatic increase in the emergence of antibiotic-resistant bacterial strains, which has made antibiotic choices for infection control increasingly limited and more expensive. In the U.S. alone, antibiotic-resistant bacteria cause at least 2 million infections and 23,000 deaths a year resulting in a $55-70 billion per year economic impact. Antibiotics are critical to the success of surgical procedures including orthopedic prosthetic surgeries, and antibiotic resistance is occurring in nearly all bacteria that infect people, including the most common bacteria that cause orthopedic infections, such as Staphylococcus aureus (S. aureus). Most clinical cases of orthopedic surgeries have shown that patients infected with antibiotic-resistant bacteria, such as methicillin-resistant S. aureus (MRSA), are associated with increased morbidity and mortality. This paper reviews the severity of antibiotic resistance at the global scale, the consequences of antibiotic resistance, and the pathways bacteria used to develop antibiotic resistance. It highlights the opportunities and challenges in limiting antibiotic resistance through approaches like the development of novel, non-drug approaches to reduce bacteria functions related to orthopedic implant-associated infections. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:22-32, 2018.201828722231
668860.9945Antibiotic resistant bacteria: A bibliometric review of literature. Antibiotic-resistant bacteria (ARB) are a serious threat to the health of people and the ecological environment. With this problem becoming more and more serious, more countries made research on the ARB, and the research number has been sharply increased particularly over the past decade. Therefore, it is quite necessary to globally retrace relevant researches on the ARB published from 2010 to 2020. This will help researchers to understand the current research situation, research trends and research hotspots in this field. This paper uses bibliometrics to examine publications in the field of ARB from 2010 to 2020 that were retrieved from the Web of Science (WOS). Our study performed a statistical analysis of the countries, institutions, journals, authors, research areas, author keywords, Essential Science Indicators (ESI) highly cited papers, and ESI hotspots papers to provide an overview of the ARB field as well as research trends, research hotspots, and future research directions in the field. The results showed that the number of related studies is increasing year by year; the USA is most published in the field of ARB; China is the most active in this field in the recent years; the Chinese Acad Sci published the most articles; Sci. Total Environ. published the greatest number of articles; CM Manaia has the most contributions; Environmental Sciences and Ecology is the most popular research area; and "antibiotic resistance," "antibiotics," and "antibiotic resistance genes" were the most frequently occurring author keywords. A citation analysis showed that aquatic environment-related antibiotic resistance is a key research area in this field, while antimicrobial nanomaterial-related research is a recent popular topic.202236466520
489570.9945Drug resistance in leprosy: An update following 70years of chemotherapy. Leprosy is one of the oldest infectious diseases, reported for more than 2000years. Leprosy elimination goal as a public health problem set by the World Health Organization, aiming for a global prevalence rate<1 patient in a population of 10,000, was achieved in 2000 mainly thanks to the worldwide use of leprosy drugs starting in the 1980s and their access at no cost for patients since 1995. However, around 200,000 new cases are still reported each year, particularly in India, Brazil, and Indonesia. As with other bacteria of medical interest, antimicrobial resistance is observed in Mycobacterium leprae strains in several parts of the world, despite multidrug therapy being the recommended standard leprosy treatment to avoid resistance selection since 1982. Therefore, identifying and monitoring resistance is necessary. We provide an overview of the historical facts that led to the current drug resistance situation, the antibiotics effective against M. leprae, their mechanisms of action and resistance, and resistance detection methods. We also discuss therapeutic management of the resistant cases, new genes with potential roles in drug resistance and bacterial adaptation, new drugs under investigation, and the risk for resistance selection with the chemoprophylaxis measures.202235483633
979380.9945Recent Review on Subclass B1 Metallo-β-lactamases Inhibitors: Sword for Antimicrobial Resistance. An emerging crisis of antibiotic resistance for microbial pathogens is alarming all the nations, posing a global threat to human health. The production of the metalloβ-lactamase enzyme is the most powerful strategy of bacteria to produce resistance. An efficient way to combat this global health threat is the development of broad/non-specific type of metalloβ-lactamase inhibitors, which can inhibit the different isoforms of the enzyme. Till date, there are no clinically active drugs against metallo- β-lactamase. The lack of efficient drug molecules against MBLs carrying bacteria requires continuous research efforts to overcome the problem of multidrug-resistance bacteria. The present review will discuss the clinically potent molecules against different variants of B1 metalloβ-lactamase.201930556502
944690.9945Newer antibiotics for the treatment of respiratory tract infections. PURPOSE OF REVIEW: In this review, we highlight some of the developments achieved over the past 2 years in the field of novel antimicrobial compounds. RECENT FINDINGS: Modification of existing compound classes to create more powerful compounds capable of overcoming pathogen resistance and the introduction of completely new classes of antibiotics and inhibitors of new bacterial targets or inhibitors of genes relating to virulence or pathogenesis are the strategies more commonly employed in pharmacologic research. Ketolides, oxazolidinones, streptogramins, glycylcyclines, and peptide deformylase inhibitors are among the most promising classes of antibiotics. Recently, several lines of research have documented that it is effective to target the infection process rather than killing bacteria. This is important because it is likely that such a therapeutic strategy could ablate infection without inducing resistance. SUMMARY: Emergence of resistance to the antibiotics currently employed in clinical practice is a continual stimulus for further research aimed at identifying novel antimicrobial compounds. These drugs will perhaps effectively fight against bacteria that now are scarcely controlled by the traditional antimicrobial agents. Health care personnel must appreciate that only judicious use of antimicrobial drugs will prevent the further uncontrolled spread of bacterial resistance. Implementation of reference guidelines would probably be an effective way to limit antibiotic misuse.200415071370
9766100.9945Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria. Multidrug-resistant (MDR) bacteria pose a grave concern to global health, which is perpetuated by a lack of new treatments and countermeasure platforms to combat outbreaks or antibiotic resistance. To address this, we have developed a Facile Accelerated Specific Therapeutic (FAST) platform that can develop effective peptide nucleic acid (PNA) therapies against MDR bacteria within a week. Our FAST platform uses a bioinformatics toolbox to design sequence-specific PNAs targeting non-traditional pathways/genes of bacteria, then performs in-situ synthesis, validation, and efficacy testing of selected PNAs. As a proof of concept, these PNAs were tested against five MDR clinical isolates: carbapenem-resistant Escherichia coli, extended-spectrum beta-lactamase Klebsiella pneumoniae, New Delhi Metallo-beta-lactamase-1 carrying Klebsiella pneumoniae, and MDR Salmonella enterica. PNAs showed significant growth inhibition for 82% of treatments, with nearly 18% of treatments leading to greater than 97% decrease. Further, these PNAs are capable of potentiating antibiotic activity in the clinical isolates despite presence of cognate resistance genes. Finally, the FAST platform offers a novel delivery approach to overcome limited transport of PNAs into mammalian cells by repurposing the bacterial Type III secretion system in conjunction with a kill switch that is effective at eliminating 99.6% of an intracellular Salmonella infection in human epithelial cells.202133712689
4445110.9944Genomic Analysis and Resistance Mechanisms in Shigella flexneri 2a Strain 301. Shigella flexneri is one of the most prominent pathogenic bacteria in developing countries. In the battle against shigellosis and other bacterial diseases, antibiotic resistance has become an increasing global public health threat. Although the serious phenomenon of multidrug resistance (MDR) has been identified as one of the top three burdens on human health, resistance mechanisms are still poorly understood at the molecular level. In this study, we analyzed genomic data and the evolution of resistance in Shigella flexneri under sequential selection stress from three separate antibiotics: ciprofloxacin (CIP), ceftriaxone (CRO), and tetracycline. Through whole-genome sequencing, 82 chromosomal antibiotic resistance genes were identified. Re-sequencing of the evolved populations identified single nucleotide polymorphisms (SNPs) that contributed to MDR and SNPs that were specific to a single drug. A total of 40 SNPs in 8 genes and 3 intergenic regions, including mutations in metG (L582R) and 1538924, 1538924, and 1538924, appeared under each antibiotic. Several nonsynonymous mutations in gyrB (S464Y), ydgA (E378A), rob (R156H), and narX (K75E) were observed under selective pressure from CIP or CRO. Based on a bioinformatic analysis and previous reports, we discuss the contribution of these mutated genes to resistance. Therefore, more circumspect selection and use of antimicrobial drugs for treating shigellosis is necessary.201828853989
3747120.994440 years of veterinary papers in JAC - what have we learnt? This review, for the occasion of the 40th anniversary of the Journal of Antimicrobial Chemotherapy (JAC), gives an overview of the manuscripts related to veterinary bacteriology published in the journal in the past 40 years with a focus on 'One Health' aspects. From 1975 to 2000 the number of manuscripts related to veterinary medicine was limited, but thereafter, the number steadily increased. Most manuscripts published were related to food-producing animals, but companion animals and minor species were also covered. Subjects included antimicrobial usage in animals and the consequences for human medicine, new resistance genes and mechanisms, the prevalence and epidemiology of antimicrobial resistance, and the emergence of resistant bacteria in animals with zoonotic potential such as livestock-associated MRSA (LA-MRSA), methicillin-resistant Staphylococcus pseudintermedius (MRSP) and ESBL-producing Enterobacteriaceae. These manuscripts have added to our knowledge on the risks of transmission of resistant bacteria from animals to humans and the importance of the prudent use of antimicrobial agents in veterinary medicine.201627660260
8180130.9944Harnessing Nanoparticles to Overcome Antimicrobial Resistance: Promises and Challenges. The rise of antimicrobial resistance (AMR) has become a serious global health issue that kills millions of people each year globally. AMR developed in bacteria is difficult to treat and poses a challenge to clinicians. Bacteria develop resistance through a variety of processes, including biofilm growth, targeted area alterations, and therapeutic drug alteration, prolonging the period they remain within cells, where antibiotics are useless at therapeutic levels. This rise in resistance is linked to increased illness and death, highlighting the urgent need for effective solutions to combat this growing challenge. Nanoparticles (NPs) offer unique solutions for fighting AMR bacteria. Being smaller in size with a high surface area, enhancing interaction with bacteria makes the NPs strong antibacterial agents against various infections. In this review, we have discussed the epidemiology and mechanism of AMR development. Furthermore, the role of nanoparticles as antibacterial agents, and their role in drug delivery has been addressed. Additionally, the potential, challenges, toxicity, and future prospects of nanoparticles as antibacterial agents against AMR pathogens have been discussed. The research work discussed in this review links with Sustainable Development Goal 3 (SDG-3), which aims to ensure disease-free lives and promote well-being for all ages.202539219123
9798140.9943Fight Against Antimicrobial Resistance: We Always Need New Antibacterials but for Right Bacteria. Antimicrobial resistance in bacteria is frightening, especially resistance in Gram-negative Bacteria (GNB). In 2017, the World Health Organization (WHO) published a list of 12 bacteria that represent a threat to human health, and among these, a majority of GNB. Antibiotic resistance is a complex and relatively old phenomenon that is the consequence of several factors. The first factor is the vertiginous drop in research and development of new antibacterials. In fact, many companies simply stop this R&D activity. The finding is simple: there are enough antibiotics to treat the different types of infection that clinicians face. The second factor is the appearance and spread of resistant or even multidrug-resistant bacteria. For a long time, this situation remained rather confidential, almost anecdotal. It was not until the end of the 1980s that awareness emerged. It was the time of Vancomycin-Resistance Enterococci (VRE), and the threat of Vancomycin-Resistant MRSA (Methicillin-Resistant Staphylococcus aureus). After this, there has been renewed interest but only in anti-Gram positive antibacterials. Today, the threat is GNB, and we have no new molecules with innovative mechanism of action to fight effectively against these bugs. However, the war against antimicrobial resistance is not lost. We must continue the fight, which requires a better knowledge of the mechanisms of action of anti-infectious agents and concomitantly the mechanisms of resistance of infectious agents.201931470632
9797150.9943Evaluation of Antibiotic Resistance Mechanisms in Gram-Positive Bacteria. The prevalence of resistance in Gram-positive bacterial infections is rapidly rising, presenting a pressing global challenge for both healthcare systems and economies. The WHO categorizes these bacteria into critical, high, and medium priority groups based on the urgency for developing new antibiotics. While the first priority pathogen list was issued in 2017, the 2024 list remains largely unchanged. Despite six years having passed, the progress that has been made in developing novel treatment approaches remains insufficient, allowing antimicrobial resistance to persist and worsen on a global scale. Various strategies have been implemented to address this growing threat by targeting specific resistance mechanisms. This review evaluates antimicrobial resistance (AMR) in Gram-positive bacteria, highlighting its critical impact on global health due to the rise of multidrug-resistant pathogens. It focuses on the unique cell wall structure of Gram-positive bacteria, which influences their identification and susceptibility to antibiotics. The review explores the mechanisms of AMR, including enzymatic inactivation, modification of drug targets, limiting drug uptake, and increased drug efflux. It also examines the resistance strategies employed by high-priority Gram-positive pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium, as identified in the WHO's 2024 priority list.202439766587
4897160.9943Rapid diagnosis of tuberculosis. Detection of drug resistance mechanisms. Tuberculosis is still a serious public health problem, with 10.8 million new cases and 1.8 million deaths worldwide in 2015. The diversity among members of the Mycobacterium tuberculosis complex, the causal agent of tuberculosis, is conducive to the design of different methods for rapid diagnosis. Mutations in the genes involved in resistance mechanisms enable the bacteria to elude the treatment. We have reviewed the methods for the rapid diagnosis of M. tuberculosis complex and the detection of susceptibility to drugs, both of which are necessary to prevent the onset of new resistance and to establish early, appropriate treatment.201728318570
9813170.9943Antibacterial Discovery: 21st Century Challenges. It has been nearly 50 years since the golden age of antibiotic discovery (1945-1975) ended; yet, we still struggle to identify novel drug targets and to deliver new chemical classes of antibiotics to replace those rendered obsolete by drug resistance. Despite herculean efforts utilizing a wide range of antibiotic discovery platform strategies, including genomics, bioinformatics, systems biology and postgenomic approaches, success has been at best incremental. Obviously, finding new classes of antibiotics is really hard, so repeating the old strategies, while expecting different outcomes, seems to boarder on insanity. The key questions dealt with in this review include: (1) If mutation based drug resistance is the major challenge to any new antibiotic, is it possible to find drug targets and new chemical entities that can escape this outcome; (2) Is the number of novel chemical classes of antibacterials limited by the number of broad spectrum drug targets; and (3) If true, then should we focus efforts on subgroups of pathogens like Gram negative or positive bacteria only, anaerobic bacteria or other group where the range of common essential genes is likely greater?. This review also provides some examples of existing drug targets that appear to escape the specter of mutation based drug resistance, and provides examples of some intermediate spectrum strategies as well as modern molecular and genomic approaches likely to improve the odds of delivering 21st century medicines to combat multidrug resistant pathogens.202032353943
4176180.9943Plants with Antimicrobial Activity Growing in Italy: A Pathogen-Driven Systematic Review for Green Veterinary Pharmacology Applications. Drug resistance threatening humans may be linked with antimicrobial and anthelmintic resistance in other species, especially among farm animals and, more in general, in the entire environment. From this perspective, Green Veterinary Pharmacology was proven successful for the control of parasites in small ruminants and for the control of other pests such as varroa in bee farming. As in anthelmintic resistance, antimicrobial resistance (AMR) represents one of the major challenges against the successful treatment of infectious diseases, and antimicrobials use in agriculture contributes to the spread of more AMR bacterial phenotypes, genes, and proteins. With this systematic review, we list Italian plants with documented antimicrobial activity against possible pathogenic microbes. Methods: The literature search included all the manuscripts published since 1990 in PubMed, Web of Science, and Scopus using the keywords (i) "antimicrobial, plants, Italy"; (ii) "antibacterial, plant, Italy"; (iii) "essential oil, antibacterial, Italy"; (iv) "essential oil, antimicrobial, Italy"; (v) "methanol extract, antibacterial, Italy"; (vi) "methanol extract, antimicrobial, Italy". Results: In total, 105 manuscripts that documented the inhibitory effect of plants growing in Italy against bacteria were included. One hundred thirty-five plants were recorded as effective against Gram+ bacteria, and 88 against Gram-. This will provide a ready-to-use comprehensive tool to be further tested against the indicated list of pathogens and will suggest new alternative strategies against bacterial pathogens to be employed in Green Veterinary Pharmacology applications.202235884173
8179190.9943Nanotechnology as a Promising Approach to Combat Multidrug Resistant Bacteria: A Comprehensive Review and Future Perspectives. The wide spread of antibiotic resistance has been alarming in recent years and poses a serious global hazard to public health as it leads to millions of deaths all over the world. The wide spread of resistance and sharing resistance genes between different types of bacteria led to emergence of multidrug resistant (MDR) microorganisms. This problem is exacerbated when microorganisms create biofilms, which can boost bacterial resistance by up to 1000-fold and increase the emergence of MDR infections. The absence of novel and potent antimicrobial compounds is linked to the rise of multidrug resistance. This has sparked international efforts to develop new and improved antimicrobial agents as well as innovative and efficient techniques for antibiotic administration and targeting. There is an evolution in nanotechnology in recent years in treatment and prevention of the biofilm formation and MDR infection. The development of nanomaterial-based therapeutics, which could overcome current pathways linked to acquired drug resistance, is a hopeful strategy for treating difficult-to-treat bacterial infections. Additionally, nanoparticles' distinct size and physical characteristics enable them to target biofilms and treat resistant pathogens. This review highlights the current advances in nanotechnology to combat MDR and biofilm infection. In addition, it provides insight on development and mechanisms of antibiotic resistance, spread of MDR and XDR infection, and development of nanoparticles and mechanisms of their antibacterial activity. Moreover, this review considers the difference between free antibiotics and nanoantibiotics, and the synergistic effect of nanoantibiotics to combat planktonic bacteria, intracellular bacteria and biofilm. Finally, we will discuss the strength and limitations of the application of nanotechnology against bacterial infection and future perspectives.202336830949