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Current Pharmaceutical Design 2022One of the major global health care crises in the 21st century is antibiotic resistance. Almost all clinically used antibiotics have resistance emerging to them.... (Review)
Review
One of the major global health care crises in the 21st century is antibiotic resistance. Almost all clinically used antibiotics have resistance emerging to them. Antibiotic Resistance can be regarded as the 'Faceless Pandemic' that has enthralled the entire world. It has become peremptory to develop treatment options as an alternative to antibiotic therapy for combating antibiotic-resistant pathogens. A clearer understanding of antibiotic resistance is required to prevent the rapid spread of antibiotic-resistant genes and the re-emergence of infections. The present review provides an insight into the different classifications and modes of action of antibiotics to understand how the hosts develop resistance to them. In addition, the association of genetics in the development of antibiotic resistance and environmental factors has also been discussed, emphasizing developing action plans to counter this "quiescent pandemic". It is also pertinent to create models that can predict the early resistance so that treatment strategies may build up in advance with the evolving resistance.
Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Humans
PubMed: 35676839
DOI: 10.2174/1381612828666220608120238 -
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 -
The New Microbiologica Jul 2007Antibiotics were initially viewed as "wonder drugs" primarily because they were introduced at a time when only surgical drainage or spontaneous cures were available to... (Review)
Review
Antibiotics were initially viewed as "wonder drugs" primarily because they were introduced at a time when only surgical drainage or spontaneous cures were available to treat serious bacterial infections. During the five or six decades since their introduction, several classes of these drugs became available including sulfonamides and trimethoprim, penicillins, cephalosporins, chloramphenicol, tetracyclines, colimycins, macrolides, lincosamides, streptogramins, rifamycins, glycopeptides, aminoglycosides, fluoroquinolones, oxazolidinones, glycylglycines, lipoglycopeptides, and variations on these themes. Unfortunately, through a variety of mechanisms and perhaps as a result of their profligate use, many bacterial groups are exhibiting resistance to these antibiotics. At present, most bacterial infections can still be treated with available antibiotics used alone or in combination, but increasing numbers of clinical failures with the current armamentarium can be expected. Optimizing drug dosing and duration might help minimize the emergence of resistance in some situations. However, the future could look dim, as there are relatively few new agents on the horizon. A bold new look for antibacterial targets is needed. Surely our scientific abilities are up to this challenge. New approaches to antimicrobial chemotherapy are needed if we are to survive the increasing rates of antibiotic resistance predicted for the future.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Microbial; Humans
PubMed: 17802919
DOI: No ID Found -
Orthopaedics & Traumatology, Surgery &... Feb 2021When all rules of hygiene have been scrupulously applied, antibiotic prophylaxis (ABP) is the one remaining means of further reducing surgical site infection risk. Its... (Review)
Review
When all rules of hygiene have been scrupulously applied, antibiotic prophylaxis (ABP) is the one remaining means of further reducing surgical site infection risk. Its efficacy in major orthopedic surgical procedures is proven. Guidelines for indications and ABP systemic administration have been long established and are able to address many questions. By extrapolation, the same protocols apply in closed fractures, whereas they are less certain in open fractures, where successive and still incomplete reassessments have been made. There are no specific ABP protocols in implant revision for mechanical or infectious causes or in high-grade open fractures, despite the high associated risk of surgical site infection. All means of prophylaxis need exploring in these contexts: various molecule combinations, and various local applications. Although ideas are by no means lacking, levels of evidence are low or undetermined. Awaiting more objective data, the focus has to be on the quality of implementation. It is easy enough to conceive of ABP in terms of the tissue pharmacokinetics of the antibiotic(s), but real-life implementation is a real organizational challenge. Optimizing practices in clearly defined indications is still the prime objective for surgical ABP.
Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Humans; Orthopedic Procedures; Orthopedics; Surgical Wound Infection; Traumatology
PubMed: 33316449
DOI: 10.1016/j.otsr.2020.102751 -
APMIS : Acta Pathologica,... May 2019The discovery of antibiotic drugs is considered one of the previous century's most important medical discoveries (Medicine's 10 greatest discoveries. New Haven, CT: Yale... (Review)
Review
The discovery of antibiotic drugs is considered one of the previous century's most important medical discoveries (Medicine's 10 greatest discoveries. New Haven, CT: Yale University Press, 1998: 263). Appropriate use of antibiotics saves millions of lives each year and prevents infectious complications for numerous people. Still, infections kill unacceptable many people around the world, even in developed countries with easy access to most antibiotic drugs. Optimal use of antibiotics is dependent on the identification of primary and secondary focus, and knowledge on which pathogens to expect in a specific infectious syndrome and information on general patterns of regional antibiotic resistance. Furthermore, sampling for microbiological analysis, knowledge of patient immune status and organ functions, travel history, pharmacokinetics and -dynamics of the different antibiotics and possible biofilm formation are among several factors involved in antibiotic therapy of infectious diseases. The present review aims at describing important considerations when using antibacterial antibiotics and to describe how this is becoming substantially more personalized. The parameters relevant in considering the optimal use of antibiotics to treat infections are shown in Fig. 1 - leading to the most relevant antibiotic therapy for that specific patient. To illustrate this subject, the present review's focus will be on challenges with optimal dosing of antibiotics and risks of underdosing. Especially, in cases highly challenging for achieving the aimed antibiotic effect against bacterial infections - this includes augmented renal clearance (ARC) in sepsis, dosing challenges of antibiotics in pregnancy and against biofilm infections.
Topics: Anti-Bacterial Agents; Biofilms; Drug Monitoring; Female; Humans; Kidney; Microbial Sensitivity Tests; Precision Medicine; Pregnancy
PubMed: 30983040
DOI: 10.1111/apm.12951 -
Biochemical Pharmacology Jun 2017An ideal antibiotic is an antibacterial agent that kills or inhibits the growth of all harmful bacteria in a host, regardless of site of infection without affecting... (Review)
Review
An ideal antibiotic is an antibacterial agent that kills or inhibits the growth of all harmful bacteria in a host, regardless of site of infection without affecting beneficial gut microbes (gut flora) or causing undue toxicity to the host. Sadly, no such antibiotics exist. What exist are many effective Gram-positive antibacterial agents as well as broad-spectrum agents that provide treatment of certain Gram-negative bacteria but not holistic treatment of all bacteria. However effectiveness of all antibacterial agents is being rapidly eroded due to resistance. This viewpoint provides an overview of today's antibiotics, challenges and potential path forward of discovery and development of new (ideal) antibiotics.
Topics: Anti-Bacterial Agents; Drug Discovery; Gram-Negative Bacteria; Humans; Microbial Sensitivity Tests
PubMed: 28087253
DOI: 10.1016/j.bcp.2017.01.003 -
Accounts of Chemical Research May 2021Rifamycin antibiotics include the WHO essential medicines rifampin, rifabutin, and rifapentine. These are semisynthetic derivatives of the natural product rifamycins,... (Review)
Review
Rifamycin antibiotics include the WHO essential medicines rifampin, rifabutin, and rifapentine. These are semisynthetic derivatives of the natural product rifamycins, originally isolated from the soil bacterium . These antibiotics are primarily used to treat mycobacterial infections, including tuberculosis. Rifamycins act by binding to the β-subunit of bacterial RNA polymerase, inhibiting transcription, which results in cell death. These antibiotics consist of a naphthalene core spanned by a polyketide bridge. This structure presents a unique 3D configuration that engages RNA polymerase through a series of hydrogen bonds between hydroxyl groups linked to the naphthalene core and C21 and C23 of the bridge. This binding occurs not in the enzyme active site where template-directed RNA synthesis occurs but instead in the RNA exit tunnel, thereby blocking productive formation of full-length RNA. In their clinical use to treat tuberculosis, resistance to rifamycin antibiotics arises principally from point mutations in RNA polymerase that decrease the antibiotic's affinity for the binding site in the RNA exit tunnel. In contrast, the rifamycin resistome of environmental mycobacteria and actinomycetes is much richer and diverse. In these organisms, rifamycin resistance includes many different enzymatic mechanisms that modify and alter the antibiotic directly, thereby inactivating it. These enzymes include ADP ribosyltransferases, glycosyltransferases, phosphotransferases, and monooxygenases.ADP ribosyltransferases catalyze group transfer of ADP ribose from the cofactor NAD, which is more commonly deployed for metabolic redox reactions. ADP ribose is transferred to the hydroxyl linked to C23 of the antibiotic, thereby sterically blocking productive interaction with RNA polymerase. Like ADP ribosyltransferases, rifamycin glycosyl transferases also modify the hydroxyl of position C23 of rifamycins, transferring a glucose moiety from the donor molecule UDP-glucose. Unlike other antibiotic resistance kinases that transfer the γ-phosphate of ATP to inactivate antibiotics such as aminoglycosides or macrolides, rifamycin phosphotransferases are ATP-dependent dikinases. These enzymes transfer the β-phosphate of ATP to the C21 hydroxyl of the rifamycin bridge. The result is modification of a critical RNA polymerase binding group that blocks productive complex formation. On the other hand, rifamycin monooxygenases are FAD-dependent enzymes that hydroxylate the naphthoquinone core. The result of this modification is untethering of the chain from the naphthyl moiety, disrupting the essential 3D shape necessary for productive RNA polymerase binding and inhibition that leads to cell death.All of these enzymes have homologues in bacterial metabolism that either are their direct precursors or share common ancestors to the resistance enzyme. The diversity of these resistance mechanisms, often redundant in individual bacterial isolates, speaks to the importance of protecting RNA polymerase from these compounds and validates this enzyme as a critical antibiotic target.
Topics: Amycolatopsis; Anti-Bacterial Agents; Drug Resistance, Bacterial; RNA-Dependent RNA Polymerase; Rifamycins
PubMed: 33877820
DOI: 10.1021/acs.accounts.1c00048 -
Indian Journal of Pediatrics Nov 2020This article can rightly be called 'the rise of the microbial phoenix'; for, all the microbial infections whose doomsday was predicted with the discovery of antibiotics,... (Review)
Review
This article can rightly be called 'the rise of the microbial phoenix'; for, all the microbial infections whose doomsday was predicted with the discovery of antibiotics, have thumbed their noses at mankind and reemerged phoenix like. The hubris generated by Sir Alexander Fleming's discovery of Penicillin in 1928, exemplified best by the comment by William H Stewart, the US Surgeon General in 1967, "It is time to close the books on infectious diseases" has been replaced by the realisation that the threat of antibiotic resistance is, in the words of the Chief Medical Officer of England, Dame Sally Davies, "just as important and deadly as climate change and international terrorism". Antimicrobial resistance threatens to negate all the major medical advances of the last century because antimicrobial use is linked to many other fields like organ transplantation and cancer chemotherapy. Antibiotic resistance genes have been there since ancient times in response to naturally occurring antibiotics. Modern medicine has only driven further evolution of antimicrobial resistance by use, misuse, overuse and abuse of antibiotics. Resistant bacteria proliferate by natural selection when their drug sensitive comrades are removed by antibiotics. In this article the authors discuss the various causes of antimicrobial resistance and dwell in some detail on antibiotic resistance in gram-positive and gram-negative organisms. Finally they stress on the important role clinicians have in limiting the development and spread of antimicrobial resistance.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Humans
PubMed: 32026301
DOI: 10.1007/s12098-019-03180-3 -
Current Topics in Microbiology and... 2016For thousands of years people were delivered helplessly to various kinds of infections, which often reached epidemic proportions and have cost the lives of millions of... (Review)
Review
For thousands of years people were delivered helplessly to various kinds of infections, which often reached epidemic proportions and have cost the lives of millions of people. This is precisely the age since mankind has been thinking of infectious diseases and the question of their causes. However, due to a lack of knowledge, the search for strategies to fight, heal, and prevent the spread of communicable diseases was unsuccessful for a long time. It was not until the discovery of the healing effects of (antibiotic producing) molds, the first microscopic observations of microorganisms in the seventeenth century, the refutation of the abiogenesis theory, and the dissolution of the question "What is the nature of infectious diseases?" that the first milestones within the history of antibiotics research were set. Then new discoveries accelerated rapidly: Bacteria could be isolated and cultured and were identified as possible agents of diseases as well as producers of bioactive metabolites. At the same time the first synthetic antibiotics were developed and shortly thereafter, thousands of synthetic substances as well as millions of soil borne bacteria and fungi were screened for bioactivity within numerous microbial laboratories of pharmaceutical companies. New antibiotic classes with different targets were discovered as on assembly line production. With the beginning of the twentieth century, many of the diseases which reached epidemic proportions at the time-e.g., cholera, syphilis, plague, tuberculosis, or typhoid fever, just to name a few, could be combatted with new discovered antibiotics. It should be considered that hundred years ago the market launch of new antibiotics was significantly faster and less complicated than today (where it takes 10-12 years in average between the discovery of a new antibiotic until the launch). After the first euphoria it was quickly realized that bacteria are able to develop, acquire, and spread numerous resistance mechanisms. Whenever a new antibiotic reached the market it did not take long until scientists observed the first resistant germs. Since the marketing of the first antibiotic there is a neck-on-neck race between scientists who discover natural or develop semisynthetic and synthetic bioactive molecules and bacteria, which have developed resistance mechanisms. The emphasis of this chapter is to give an overview of the history of antibiotics research. The situation within the pre-antibiotic era as well as in the early antibiotic era will be described until the Golden Age of Antibiotics will conclude this time travel. The most important antibiotic classes, information about their discovery, activity spectrum, mode of action, resistance mechanisms, and current application will be presented.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Biomedical Research; History, 15th Century; History, 16th Century; History, 17th Century; History, 18th Century; History, 19th Century; History, 20th Century; History, 21st Century; History, Medieval; Humans
PubMed: 27738915
DOI: 10.1007/82_2016_499 -
Current Opinion in Microbiology Oct 2022Rising antibiotic resistance and an alarmingly lean antibiotic pipeline require the adoption of novel approaches to rapidly discover new structural and functional... (Review)
Review
Rising antibiotic resistance and an alarmingly lean antibiotic pipeline require the adoption of novel approaches to rapidly discover new structural and functional classes of antibiotics. Excitingly, algorithmic approaches to antibiotic discovery are sufficiently advanced to meaningfully influence the antibiotic discovery process. Indeed, once trained on high-quality datasets, contemporary machine-learning and deep-learning models can be used to perform predictions for new antibiotics across vast chemical spaces, orders of magnitude more rapidly than compounds can be screened in the laboratory. This increases the probability of discovering new antibiotics with desirable properties. In this short review, we briefly describe the utility of contemporary machine-learning and deep-learning approaches to guide the discovery of new small-molecule antibiotics and unidentified natural products. We then propose a call to action for more open sharing of high-quality screening datasets to accelerate the rate at which forthcoming antibiotic-prediction models can be trained. Together, we aim to introduce antibiotic discoverers to a sample of recent applications of contemporary algorithmic methods to facilitate the wider adoption of these powerful computational approaches.
Topics: Anti-Bacterial Agents; Biological Products; Drug Discovery; Machine Learning
PubMed: 35963098
DOI: 10.1016/j.mib.2022.102190