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EMBO Reports Dec 2020Antimicrobial resistance (AMR) and persistence are associated with an elevated risk of treatment failure and relapsing infections. They are thus important drivers of... (Review)
Review
Antimicrobial resistance (AMR) and persistence are associated with an elevated risk of treatment failure and relapsing infections. They are thus important drivers of increased morbidity and mortality rates resulting in growing healthcare costs. Antibiotic resistance is readily identifiable with standard microbiological assays, and the threat imposed by antibiotic resistance has been well recognized. Measures aiming to reduce resistance development and spreading of resistant bacteria are being enforced. However, the phenomenon of bacteria surviving antibiotic exposure despite being fully susceptible, so-called antibiotic persistence, is still largely underestimated. In contrast to antibiotic resistance, antibiotic persistence is difficult to measure and therefore often missed, potentially leading to treatment failures. In this review, we focus on bacterial mechanisms allowing evasion of antibiotic killing and discuss their implications on human health. We describe the relationship between antibiotic persistence and bacterial heterogeneity and discuss recent studies that link bacterial persistence and tolerance with the evolution of antibiotic resistance. Finally, we review persister detection methods, novel strategies aiming at eradicating bacterial persisters and the latest advances in the development of new antibiotics.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Drug Resistance, Microbial; Humans
PubMed: 33400359
DOI: 10.15252/embr.202051034 -
Nature Reviews. Microbiology May 2022Antibiotic resistance is a global health challenge, involving the transfer of bacteria and genes between humans, animals and the environment. Although multiple barriers... (Review)
Review
Antibiotic resistance is a global health challenge, involving the transfer of bacteria and genes between humans, animals and the environment. Although multiple barriers restrict the flow of both bacteria and genes, pathogens recurrently acquire new resistance factors from other species, thereby reducing our ability to prevent and treat bacterial infections. Evolutionary events that lead to the emergence of new resistance factors in pathogens are rare and challenging to predict, but may be associated with vast ramifications. Transmission events of already widespread resistant strains are, on the other hand, common, quantifiable and more predictable, but the consequences of each event are limited. Quantifying the pathways and identifying the drivers of and bottlenecks for environmental evolution and transmission of antibiotic resistance are key components to understand and manage the resistance crisis as a whole. In this Review, we present our current understanding of the roles of the environment, including antibiotic pollution, in resistance evolution, in transmission and as a mere reflection of the regional antibiotic resistance situation in the clinic. We provide a perspective on current evidence, describe risk scenarios, discuss methods for surveillance and the assessment of potential drivers, and finally identify some actions to mitigate risks.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Bacterial; Drug Resistance, Microbial
PubMed: 34737424
DOI: 10.1038/s41579-021-00649-x -
Brazilian Journal of Microbiology :... Dec 2021The assembly of microorganisms over a surface and their ability to develop resistance against available antibiotics are major concerns of interest. To survive against... (Review)
Review
The assembly of microorganisms over a surface and their ability to develop resistance against available antibiotics are major concerns of interest. To survive against harsh environmental conditions including known antibiotics, the microorganisms form a unique structure, referred to as biofilm. The mechanism of biofilm formation is triggered and regulated by quorum sensing, hostile environmental conditions, nutrient availability, hydrodynamic conditions, cell-to-cell communication, signaling cascades, and secondary messengers. Antibiotic resistance, escape of microbes from the body's immune system, recalcitrant infections, biofilm-associated deaths, and food spoilage are some of the problems associated with microbial biofilms which pose a threat to humans, veterinary, and food processing sectors. In this review, we focus in detail on biofilm formation, its architecture, composition, genes and signaling cascades involved, and multifold antibiotic resistance exhibited by microorganisms dwelling within biofilms. We also highlight different physical, chemical, and biological biofilm control strategies including those based on plant products. So, this review aims at providing researchers the knowledge regarding recent advances on the mechanisms involved in biofilm formation at the molecular level as well as the emergent method used to get rid of antibiotic-resistant and life-threatening biofilms.
Topics: Anti-Bacterial Agents; Bacterial Physiological Phenomena; Biofilms; Drug Resistance, Microbial; Quorum Sensing
PubMed: 34558029
DOI: 10.1007/s42770-021-00624-x -
Frontiers in Cellular and Infection... 2022Both, antibiotic persistence and antibiotic resistance characterize phenotypes of survival in which a bacterial cell becomes insensitive to one (or even) more... (Review)
Review
Both, antibiotic persistence and antibiotic resistance characterize phenotypes of survival in which a bacterial cell becomes insensitive to one (or even) more antibiotic(s). However, the molecular basis for these two antibiotic-tolerant phenotypes is fundamentally different. Whereas antibiotic resistance is genetically determined and hence represents a rather stable phenotype, antibiotic persistence marks a transient physiological state triggered by various stress-inducing conditions that switches back to the original antibiotic sensitive state once the environmental situation improves. The molecular basics of antibiotic resistance are in principle well understood. This is not the case for antibiotic persistence. Under all culture conditions, there is a stochastically formed, subpopulation of persister cells in bacterial populations, the size of which depends on the culture conditions. The proportion of persisters in a bacterial population increases under different stress conditions, including treatment with bactericidal antibiotics (BCAs). Various models have been proposed to explain the formation of persistence in bacteria. We recently hypothesized that all physiological culture conditions leading to persistence converge in the inability of the bacteria to re-initiate a new round of DNA replication caused by an insufficient level of the initiator complex ATP-DnaA and hence by the lack of formation of a functional orisome. Here, we extend this hypothesis by proposing that in this persistence state the bacteria become more susceptible to mutation-based antibiotic resistance provided they are equipped with error-prone DNA repair functions. This is - in our opinion - in particular the case when such bacterial populations are exposed to BCAs.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Drug Resistance, Microbial
PubMed: 35928205
DOI: 10.3389/fcimb.2022.900848 -
Antimicrobial Agents and Chemotherapy Jan 2020The discovery of antibiotics in the last century is considered one of the most important achievements in the history of medicine. Antibiotic usage has significantly... (Review)
Review
The discovery of antibiotics in the last century is considered one of the most important achievements in the history of medicine. Antibiotic usage has significantly reduced morbidity and mortality associated with bacterial infections. However, inappropriate use of antibiotics has led to emergence of antibiotic resistance at an alarming rate. Antibiotic resistance is regarded as a major health care challenge of this century. Despite extensive research, well-documented biochemical mechanisms and genetic changes fail to fully explain mechanisms underlying antibiotic resistance. Several recent reports suggest a key role for epigenetics in the development of antibiotic resistance in bacteria. The intrinsic heterogeneity as well as transient nature of epigenetic inheritance provides a plausible backdrop for high-paced emergence of drug resistance in bacteria. The methylation of adenines and cytosines can influence mutation rates in bacterial genomes, thus modulating antibiotic susceptibility. In this review, we discuss a plethora of recently discovered epigenetic mechanisms and their emerging roles in antibiotic resistance. We also highlight specific epigenetic mechanisms that merit further investigation for their role in antibiotic resistance.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Microbial; Epigenesis, Genetic; Humans
PubMed: 31740560
DOI: 10.1128/AAC.02225-19 -
Journal of Molecular Biology Aug 2019The biosynthesis of antibiotics and self-protection mechanisms employed by antibiotic producers are an integral part of the growing antibiotic resistance threat. The... (Review)
Review
The biosynthesis of antibiotics and self-protection mechanisms employed by antibiotic producers are an integral part of the growing antibiotic resistance threat. The origins of clinically relevant antibiotic resistance genes found in human pathogens have been traced to ancient microbial producers of antibiotics in natural environments. Widespread and frequent antibiotic use amplifies environmental pools of antibiotic resistance genes and increases the likelihood for the selection of a resistance event in human pathogens. This perspective will provide an overview of the origins of antibiotic resistance to highlight the crossroads of antibiotic biosynthesis and producer self-protection that result in clinically relevant resistance mechanisms. Some case studies of synergistic antibiotic combinations, adjuvants, and hybrid antibiotics will also be presented to show how native antibiotic producers manage the emergence of antibiotic resistance.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Biological Evolution; Biological Products; Carrier Proteins; Drug Combinations; Drug Discovery; Drug Resistance, Microbial; Drug Synergism; Environment; Humans; Kinetics; Metagenomics; Thermodynamics
PubMed: 31288031
DOI: 10.1016/j.jmb.2019.06.033 -
Molecules (Basel, Switzerland) Dec 2020Fluoroquinolones (FQs) are arguably among the most successful antibiotics of recent times. They have enjoyed over 30 years of clinical usage and become essential tools... (Review)
Review
Fluoroquinolones (FQs) are arguably among the most successful antibiotics of recent times. They have enjoyed over 30 years of clinical usage and become essential tools in the armoury of clinical treatments. FQs target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, where they stabilise a covalent enzyme-DNA complex in which the DNA is cleaved in both strands. This leads to cell death and turns out to be a very effective way of killing bacteria. However, resistance to FQs is increasingly problematic, and alternative compounds are urgently needed. Here, we review the mechanisms of action of FQs and discuss the potential pathways leading to cell death. We also discuss quinolone resistance and how quinolone treatment can lead to resistance to non-quinolone antibiotics.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Humans; Quinolones
PubMed: 33271787
DOI: 10.3390/molecules25235662 -
International Microbiology : the... Nov 2021We are living in a society of fear, where the objectivity in estimating risks is distorted by the media and the interested parties. During more than half of a century,... (Review)
Review
We are living in a society of fear, where the objectivity in estimating risks is distorted by the media and the interested parties. During more than half of a century, the feeling of antibiotic resistance as an apocalyptic phenomenon able to push our society to the high mortality rates caused by infectious diseases in the dark pre-antibiotic ages has been steadily rising. However, at the current status of modern medicine, at least in the high-medium income countries, mortality by lack of efficacy of the antibiotic armamentarium in the therapy of infections is a problem, but not a catastrophe. The threat of antibiotic resistance has many other aspects than failures of therapy in the individual patient. Among them, the increase in the frequency of severe and potentially lethal infections, as bacteremia, the population biology alterations of the healthy microbiota, the global acceleration of bacterial evolution by selecting natural genetic tools mediating microbial interactions, and, most importantly, by modifying the equilibrium and composition of environmental microbial communities. All these threats have huge implications for human health as members of a Biosphere entirely rooted in a menaced microbiosphere.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Drug Resistance, Microbial; Humans; Microbiota
PubMed: 34028624
DOI: 10.1007/s10123-021-00184-y -
Science (New York, N.Y.) Feb 2022Machine learning can use clinical history to lower the risk of infection recurrence.
Machine learning can use clinical history to lower the risk of infection recurrence.
Topics: Drug Resistance, Microbial; Machine Learning
PubMed: 35201873
DOI: 10.1126/science.abn9969 -
Translational Research : the Journal of... Sep 2020Extensive antibiotic use combined with poor historical drug stewardship practices have created a medical crisis in which once treatable bacterial infections are now... (Review)
Review
Extensive antibiotic use combined with poor historical drug stewardship practices have created a medical crisis in which once treatable bacterial infections are now increasingly unmanageable. To combat this, new antibiotics will need to be developed and safeguarded. An emerging class of antibiotics based upon nuclease-stable antisense technologies has proven valuable in preclinical testing against a variety of bacterial pathogens. This review describes the current state of development of antisense-based antibiotics, the mechanisms thus far employed by these compounds, and possible future avenues of research.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Gene Transfer Techniques; Humans; RNA, Antisense
PubMed: 32522669
DOI: 10.1016/j.trsl.2020.06.001