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Biochemical Pharmacology Jun 2017Most pharmaceutical companies have stopped or have severely limited investments to discover and develop new antibiotics to treat the increasing prevalence of infections... (Review)
Review
Most pharmaceutical companies have stopped or have severely limited investments to discover and develop new antibiotics to treat the increasing prevalence of infections caused by multi-drug resistant bacteria, because the return on investment has been mostly negative for antibiotics that received marketing approved in the last few decades. In contrast, a few small companies have taken on this challenge and are developing new antibiotics. This review describes those antibiotics in late-stage clinical development. Most of them belong to existing antibiotic classes and a few with a narrow spectrum of activity are novel compounds directed against novel targets. The reasons for some of the past failures to find new molecules and a path forward to help attract investments to fund discovery of new antibiotics are described.
Topics: Animals; Anti-Bacterial Agents; Drug Discovery; Drug Industry; Humans
PubMed: 27687641
DOI: 10.1016/j.bcp.2016.09.025 -
Annals of the New York Academy of... Sep 2014The spread of antibiotic-resistant pathogens requires new treatments. As the rate of development of new antibiotics has severely declined, alternatives to antibiotics... (Review)
Review
The spread of antibiotic-resistant pathogens requires new treatments. As the rate of development of new antibiotics has severely declined, alternatives to antibiotics must be considered in both animal agriculture and human medicine. Products for disease prevention are different from those for disease treatment, and examples of both are discussed here. For example, modulating the gut microbial community, either through feed additives or fecal transplantation, could be a promising way to prevent certain diseases; for disease treatment, non-antibiotic approaches include phage therapy, phage lysins, bacteriocins, and predatory bacteria. Interestingly, several of these methods augment antibiotic efficacy by improving bacterial killing and decreasing antibiotic resistance selection. Because bacteria can ultimately evolve resistance to almost any therapeutic agent, it is important to continue to use both antibiotics and their alternatives judiciously.
Topics: Animals; Anti-Bacterial Agents; Humans; Intestines; Microbiota
PubMed: 24953233
DOI: 10.1111/nyas.12468 -
Chemical Communications (Cambridge,... May 2023Antibiotic resistance is an enormous problem that is accountable for over a million deaths annually, with numbers expected to significantly increase over the coming... (Review)
Review
Antibiotic resistance is an enormous problem that is accountable for over a million deaths annually, with numbers expected to significantly increase over the coming decades. Although some of the underlying causes leading up to antibiotic resistance are well understood, many of the molecular processes involved remain elusive. To better appreciate at a molecular level how resistance emerges, customized chemical biology tools can offer a solution. This Feature Article attempts to provide an overview of the wide variety of tools that have been developed over the last decade, by highlighting some of the more illustrative examples. These include the use of fluorescent, photoaffinity and activatable antibiotics and bacterial components to start to unravel the molecular mechanisms involved in resistance. The antibiotic crisis is an eminent global threat and requires the continuous development of creative chemical tools to dissect and ultimately counteract resistance.
Topics: Drug Resistance, Microbial; Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial
PubMed: 37039397
DOI: 10.1039/d3cc00759f -
Current Opinion in Pediatrics Apr 2016Antibiotics have not only saved lives and improved outcomes, but they also influence the evolving microbiome. This review summarizes reports on neonatal infections and... (Review)
Review
PURPOSE OF REVIEW
Antibiotics have not only saved lives and improved outcomes, but they also influence the evolving microbiome. This review summarizes reports on neonatal infections and variation in antibiotic utilization, discusses the emergence of resistant organisms, and presents data from human neonates and animal models demonstrating the impact of antibiotics on the microbiome, and how microbiome alterations impact health. The importance of antibiotic stewardship is also discussed.
RECENT FINDINGS
Infections increase neonatal morbidity and mortality. Furthermore, the clinical presentation of infections can be subtle, prompting clinicians to empirically start antibiotics when infection is a possibility. Antibiotic-resistant infections are a growing problem. Cohort studies have identified extensive center variations in antibiotic usage and associations between antibiotic exposures and outcomes. Studies of antibiotic-induced microbiome alterations and downstream effects on the developing immune system have increased our understanding of the mechanisms underlying the associations between antibiotics and adverse outcomes. The emergence of resistant microorganisms and recent evidence linking antibiotic practice variations with health outcomes has led to the initiation of antibiotic stewardship programs.
SUMMARY
The review encourages practitioners to assess local antibiotic use with regard to local microbiology, and to adopt steps to reduce infections and use antibiotics wisely.
Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Bacterial; Drug Utilization; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Microbiota; Practice Patterns, Physicians'
PubMed: 26886785
DOI: 10.1097/MOP.0000000000000338 -
ACS Infectious Diseases Jun 2020Despite efforts to develop new antibiotics, antibacterial resistance still develops too fast for drug discovery to keep pace. Often, resistance against a new drug... (Review)
Review
Despite efforts to develop new antibiotics, antibacterial resistance still develops too fast for drug discovery to keep pace. Often, resistance against a new drug develops even before it reaches the market. This continued resistance crisis has demonstrated that resistance to antibiotics with single protein targets develops too rapidly to be sustainable. Most successful long-established antibiotics target more than one molecule or possess targets, which are encoded by multiple genes. This realization has motivated a change in antibiotic development toward drug candidates with multiple targets. Some mechanisms of action presuppose multiple targets or at least multiple effects, such as targeting the cytoplasmic membrane or the carrier molecule bactoprenol phosphate and are therefore particularly promising. Moreover, combination therapy approaches are being developed to break antibiotic resistance or to sensitize bacteria to antibiotic action. In this Review, we provide an overview of antibacterial multitarget approaches and the mechanisms behind them.
Topics: Anti-Bacterial Agents; Bacteria; Drug Discovery; Drug Resistance, Bacterial
PubMed: 32156116
DOI: 10.1021/acsinfecdis.0c00001 -
Expert Opinion on Emerging Drugs Dec 2019: Community-acquired pneumonia is the most common infection leading to hospitalization and death in all age groups, especially in elderly populations. Increasing... (Review)
Review
: Community-acquired pneumonia is the most common infection leading to hospitalization and death in all age groups, especially in elderly populations. Increasing antibiotic resistance among the common bacterial pathogens associated with community-acquired pneumonia, especially Streptococcus pneumoniae and staphylococci, has made its empirical treatment increasingly problematic, highlighting the need for effective antibiotic therapy.: We searched PubMed and ClinicalTrials.gov for English-language reports of phase III clinical trials conducted between 2000 and 2019 concerning the antibiotic treatment of community-acquired pneumonia. We provide a summary of the latest approved drugs for this indication and highlight emerging drugs with a potential indication.: Ceftaroline (a new cephalosporine) and omadacycline (a cycline alternative), either parenterally or orally, are the only two new antibiotics to have been approved by the FDA for the treatment of community-acquired pneumonia in the last five years. Among the antimicrobials in development, Lefamulin (the first pleuromutilin), is currently in phase III development. Among the known antibiotic classes, solithromycin (a macrolide), nemonoxacin (a quinolone), and delafloxacin and zabofloxacin (both fluoroquinolones), have been studied in phase II and III in clinical trials. The availability of these new antibiotics may offer opportunities to improve the empirical treatment for community-acquired pneumonia.
Topics: Animals; Anti-Bacterial Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Humans; Pneumonia, Bacterial
PubMed: 31657962
DOI: 10.1080/14728214.2019.1685494 -
ACS Infectious Diseases Mar 2022The paradigm of antivirulence therapy dictates that bacterial pathogens are specifically disarmed but not killed by neutralizing their virulence factors. Clearance of... (Review)
Review
The paradigm of antivirulence therapy dictates that bacterial pathogens are specifically disarmed but not killed by neutralizing their virulence factors. Clearance of the invading pathogen by the immune system is promoted. As compared to antibiotics, the pathogen-selective antivirulence drugs hold promise to minimize collateral damage to the beneficial microbiome. Also, selective pressure for resistance is expected to be lower because bacterial viability is not directly affected. Antivirulence drugs are being developed for stand-alone prophylactic and therapeutic treatments but also for combinatorial use with antibiotics. This Review focuses on drug modalities that target bacterial exotoxins after the secretion or release-upon-lysis. Exotoxins have a significant and sometimes the primary role as the disease-causing virulence factor, and thereby they are attractive targets for drug development. We describe the key pre-clinical and clinical trial data that have led to the approval of currently used exotoxin-targeted drugs, namely the monoclonal antibodies bezlotoxumab (toxin B/TcdB, ), raxibacumab (anthrax toxin, ), and obiltoxaximab (anthrax toxin, ), but also to challenges with some of the promising leads. We also highlight the recent developments in pre-clinical research sector to develop exotoxin-targeted drug modalities, i.e., monoclonal antibodies, antibody fragments, antibody mimetics, receptor analogs, neutralizing scaffolds, dominant-negative mutants, and small molecules. We describe how these exotoxin-targeted drug modalities work with high-resolution structural knowledge and highlight their advantages and disadvantages as antibiotic alternatives.
Topics: Anti-Bacterial Agents; Bacillus anthracis; Bacterial Toxins; Clostridioides difficile; Exotoxins
PubMed: 35099182
DOI: 10.1021/acsinfecdis.1c00296 -
Microbial Cell Factories Jan 2024Antibiotic-based plasmid selection and maintenance is a core tool in molecular biology; however, while convenient, this strategy has numerous drawbacks for biological...
BACKGROUND
Antibiotic-based plasmid selection and maintenance is a core tool in molecular biology; however, while convenient, this strategy has numerous drawbacks for biological manufacturing. Overuse of antibiotics and antibiotic resistance genes (ARG) contributes to the development of antimicrobial resistance, which is a growing threat to modern medicine. Antibiotics themselves are costly and therefore often omitted in fermentations, leading to plasmid loss and a corresponding loss in product yield. Furthermore, constitutive expression of a plasmid-encoded antibiotic resistance gene imposes a significant metabolic burden on the cells. For many fermentation products (e.g., in nutrition and medicine), the use of antibiotic resistance genes is subject to strict regulations and should be avoided. We present a method for plasmid selection and maintenance with stringent selection pressure that is independent of antibiotics and ARG. Furthermore, it can be used without any restrictions regarding culture medium and temperature.
RESULTS
The developed method involves modification of a bacterial strain such that an essential gene is expressed genomically under the control of an inducible promoter. A copy of the same essential gene with the endogenous promoter is supplied on a plasmid for selection. In the absence of the inducer for the genomic copy of the essential gene, cells rely on expression of the plasmid-encoded gene copy, leading to tight selection for plasmid maintenance. Induction of the genomic copy of the essential gene enables the engineered strain to be propagated in the absence of a plasmid. Here, we describe the genetic setup and demonstrate long-term, tight selection for plasmid maintenance with a variety of different plasmids and E. coli strains.
CONCLUSIONS
This method facilitates plasmid-based fermentations by eliminating the need for antibiotic selection and improving plasmid maintenance.
Topics: Anti-Bacterial Agents; Fermentation; Escherichia coli; Plasmids; Promoter Regions, Genetic
PubMed: 38212806
DOI: 10.1186/s12934-023-02291-z -
Annals of Medicine 2016Probiotics are live microorganisms, mainly belonging to the genera Lactobacillus and Bifidobacterium, although also strain of other species are commercialized, that have... (Review)
Review
Probiotics are live microorganisms, mainly belonging to the genera Lactobacillus and Bifidobacterium, although also strain of other species are commercialized, that have a beneficial effect on the host. From the perspective of antibiotic use, probiotics have been observed to reduce the risk of certain infectious disease such as certain types of diarrhea and respiratory tract infection. This may be accompanied with a reduced need of antibiotics for secondary infections. Antibiotics tend to be effective against most common diseases, but increasingly resistance is being observed among pathogens. Probiotics are specifically selected to not contribute to the spread of antibiotic resistance and not carry transferable antibiotic resistance. Concomitant use of probiotics with antibiotics has been observed to reduce the incidence, duration and/or severity of antibiotic-associated diarrhea. This contributes to better adherence to the antibiotic prescription and thereby reduces the evolution of resistance. To what extent probiotics directly reduce the spread of antibiotic resistance is still much under investigation; but maintaining a balanced microbiota during antibiotic use may certainly provide opportunities for reducing the spread of resistances. Key messages Probiotics may reduce the risk for certain infectious diseases and thereby reduce the need for antibiotics. Probiotics may reduce the risk for antibiotic-associated diarrhea Probiotics do not contribute to the spread of antibiotic resistance and may even reduce it.
Topics: Animals; Anti-Bacterial Agents; Bifidobacterium; Diarrhea; Drug Resistance, Bacterial; Humans; Incidence; Lactobacillus; Medication Adherence; Probiotics
PubMed: 27092975
DOI: 10.3109/07853890.2016.1161232 -
Biosensors May 2019Antibiotics are an important class of drugs destined for treatment of bacterial diseases. Misuses and overuses of antibiotics observed over the last decade have led to... (Review)
Review
Antibiotics are an important class of drugs destined for treatment of bacterial diseases. Misuses and overuses of antibiotics observed over the last decade have led to global problems of bacterial resistance against antibiotics (ABR). One of the crucial actions taken towards limiting the spread of antibiotics and controlling this dangerous phenomenon is the sensitive and accurate determination of antibiotics residues in body fluids, food products, and animals, as well as monitoring their presence in the environment. Immunosensors, a group of biosensors, can be considered an attractive tool because of their simplicity, rapid action, low-cost analysis, and especially, the unique selectivity arising from harnessing the antigen-antibody interaction that is the basis of immunosensor functioning. Herein, we present the recent achievements in the field of electrochemical immunosensors designed to determination of antibiotics.
Topics: Anti-Bacterial Agents; Biosensing Techniques; Electrochemical Techniques; Immunoassay
PubMed: 31052356
DOI: 10.3390/bios9020061