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Portrait of a killer: Uncovering resistance mechanisms and global spread of Acinetobacter baumannii.PLoS Pathogens Aug 2023Antibiotic resistance is a growing global concern in the field of medicine as it renders bacterial infections difficult to treat and often more severe. Acinetobacter...
Antibiotic resistance is a growing global concern in the field of medicine as it renders bacterial infections difficult to treat and often more severe. Acinetobacter baumannii is a gram-negative bacterial pathogen causing a wide range of infections, including pneumonia, sepsis, urinary tract infections, and wound infections. A. baumannii has emerged as a significant healthcare-associated pathogen due to its high level of antibiotic resistance. The global spread of antibiotic-resistant strains of A. baumannii has resulted in limited treatment options, leading to increased morbidity and mortality rates, especially in vulnerable populations such as the elderly and immunocompromised individuals, as well as longer hospital stays and higher healthcare costs. Further complicating the situation, multi- and pan-drug-resistant strains of A. baumannii are becoming increasingly common, and these deadly strains are resistant to all or almost all available antibiotics. A. baumannii employs various clever strategies to develop antibiotic resistance, including horizontal transfer of resistance genes, overexpression of inherent efflux pumps that remove drugs from the cell, intrinsic mutations, combined with natural selection under antibiotic selective pressure leading to emergence of successful resistance clones. The typical multidrug resistance phenotype of A. baumannii is, therefore, an orchestrated collimation of all these mechanisms combined with the worldwide spread of "global clones," rendering infections caused by this pathogen challenging to control and treat. To address the escalating problem of antibiotic resistance in A. baumannii, there is a need for increased surveillance, strict infection control measures, and the development of new treatment strategies, requiring a concerted effort by healthcare professionals, researchers, and policymakers.
Topics: Acinetobacter baumannii; Drug Resistance, Multiple, Bacterial; Anti-Bacterial Agents; Phenotype
PubMed: 37561719
DOI: 10.1371/journal.ppat.1011520 -
PLoS Computational Biology May 2024Multi-drug combinations to treat bacterial populations are at the forefront of approaches for infection control and prevention of antibiotic resistance. Although the...
Multi-drug combinations to treat bacterial populations are at the forefront of approaches for infection control and prevention of antibiotic resistance. Although the evolution of antibiotic resistance has been theoretically studied with mathematical population dynamics models, extensions to spatial dynamics remain rare in the literature, including in particular spatial evolution of multi-drug resistance. In this study, we propose a reaction-diffusion system that describes the multi-drug evolution of bacteria based on a drug-concentration rescaling approach. We show how the resistance to drugs in space, and the consequent adaptation of growth rate, is governed by a Price equation with diffusion, integrating features of drug interactions and collateral resistances or sensitivities to the drugs. We study spatial versions of the model where the distribution of drugs is homogeneous across space, and where the drugs vary environmentally in a piecewise-constant, linear and nonlinear manner. Although in many evolution models, per capita growth rate is a natural surrogate for fitness, in spatially-extended, potentially heterogeneous habitats, fitness is an emergent property that potentially reflects additional complexities, from boundary conditions to the specific spatial variation of growth rates. Applying concepts from perturbation theory and reaction-diffusion equations, we propose an analytical metric for characterization of average mutant fitness in the spatial system based on the principal eigenvalue of our linear problem, λ1. This enables an accurate translation from drug spatial gradients and mutant antibiotic susceptibility traits to the relative advantage of each mutant across the environment. Our approach allows one to predict the precise outcomes of selection among mutants over space, ultimately from comparing their λ1 values, which encode a critical interplay between growth functions, movement traits, habitat size and boundary conditions. Such mathematical understanding opens new avenues for multi-drug therapeutic optimization.
Topics: Anti-Bacterial Agents; Models, Biological; Drug Resistance, Multiple, Bacterial; Computational Biology; Bacteria; Computer Simulation; Drug Resistance, Multiple; Evolution, Molecular; Humans
PubMed: 38820350
DOI: 10.1371/journal.pcbi.1012098 -
Archives of Microbiology Jun 2024The increase of multiple drug resistance bacteria significantly diminishes the effectiveness of antibiotic armory and subsequently exaggerates the level of therapeutic... (Review)
Review
The increase of multiple drug resistance bacteria significantly diminishes the effectiveness of antibiotic armory and subsequently exaggerates the level of therapeutic failure. Phytoconstituents are exceptional substitutes for resistance-modifying vehicles. The plants appear to be a deep well for the discovery of novel antibacterial compounds. This is owing to the numerous enticing characteristics of plants, they are easily accessible and inexpensive, extracts or chemicals derived from plants typically have significant levels of action against infections, and they rarely cause serious adverse effects. The enormous selection of phytochemicals offers very distinct chemical structures that may provide both novel mechanisms of antimicrobial activity and deliver us with different targets in the interior of the bacterial cell. They can directly affect bacteria or act together with the crucial events of pathogenicity, in this manner decreasing the aptitude of bacteria to create resistance. Abundant phytoconstituents demonstrate various mechanisms of action toward multi drug resistance bacteria. Overall, this comprehensive review will provide insights into the potential of phytoconstituents as alternative treatments for bacterial infections, particularly those caused by multi drug resistance strains. By examining the current state of research in this area, the review will shed light on potential future directions for the development of new antimicrobial therapies.
Topics: Anti-Bacterial Agents; Phytochemicals; Bacteria; Drug Resistance, Multiple, Bacterial; Bacterial Infections; Plant Extracts; Humans
PubMed: 38913205
DOI: 10.1007/s00203-024-04035-y -
Frontiers in Bioscience (Landmark... Feb 2024Primary liver cancer is one of the most common malignant tumors with high mortality and increasing incidence worldwide. Currently, chemotherapy is an important... (Review)
Review
Primary liver cancer is one of the most common malignant tumors with high mortality and increasing incidence worldwide. Currently, chemotherapy is an important comprehensive treatment for moderate or advanced liver cancer. Despite the effective therapeutic effects initially achieved by chemotherapy, the high phenotypic and molecular heterogeneity of liver cancer cells facilitates resistance to conventional chemotherapy or targeted therapy and even leads to multidrug resistance (MDR), which is one of the major obstacles for clinical chemotherapy. Drug resistance exhibits multiple and complex molecular mechanisms to antagonize therapy under pharmacological pressure, including overexpression of drug efflux transporters, downstream adaptive response (such as apoptosis, autophagy, and endoplasmic reticulum stress), dysfunction of DNA damage repair (DDR), epigenetic modification, tumor microenvironment (TME) as well as extracellular matrix (ECM). In this paper, we summarize the recent research progress and intervention strategies for drug resistance in hepatocellular carcinoma (HCC), which will provide a promising therapeutic strategy for overcoming MDR in liver cancer.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Apoptosis; Tumor Microenvironment
PubMed: 38420802
DOI: 10.31083/j.fbl2902052 -
Emergency Medicine Clinics of North... May 2024(Basic awareness and understanding of antimicrobial resistance and prevailing mechanisms can aid emergency physicians in providing appropriate care to patients with... (Review)
Review
(Basic awareness and understanding of antimicrobial resistance and prevailing mechanisms can aid emergency physicians in providing appropriate care to patients with infections due to a multidrug-resistant organism (MDRO). Empiric treatment of MDRO infections should be approached with caution and guided by the most likely pathogens based on differential diagnosis, severity of the illness, suspected source of infection, patient-specific factors, and local antibiotic susceptibility patterns. Newer broad-spectrum antibiotics should be reserved for critically ill patients where there is a high likelihood of infection with an MDRO.).
Topics: Humans; Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Emergency Service, Hospital
PubMed: 38641399
DOI: 10.1016/j.emc.2024.02.005 -
Saudi Medical Journal Aug 2023A significant opportunistic pathogen, () has evolved mechanisms of resistance to a wide variety of antimicrobials, including carbapenems. In this article, we assessed... (Review)
Review
A significant opportunistic pathogen, () has evolved mechanisms of resistance to a wide variety of antimicrobials, including carbapenems. In this article, we assessed the prevalence, risk factors, antimicrobial sensitivity, and resistance mechanisms among in several locations in Saudi Arabia. Hospital-acquired infections caused by were prevalent in the country due to a variety of reasons, such as the high number of critically ill patients, the frequency of gastrointestinal colonization, and the widespread use of antimicrobial medications. There has been an increase in the frequency of strains that are resistant to several antimicrobials, including carbapenems. Hospitals are a breeding ground for multidrug-resistant due to the widespread use of broad-spectrum antibiotics, the potential for patient-to-patient transmission of the bacteria, the high risk of infection during invasive intensive care unit procedures, and the high frequency with which diabetic and cancer patients in hospitals undergo invasive diagnostic and therapeutic procedures. Combinations of colistin and tigecycline with carbapenems or other antibiotics remain the best treatment option and are relatively safe to treat patients with multidrug resistance (MDR) infections, despite the rising incidence of resistance to these drugs observed in many hospitals. The prevalence of multidrug-resistant in Saudi hospitals calls for in-depth research into the underlying molecular mechanisms of multidrug resistance. In addition, a better understanding of resistance patterns and the establishment of a treatment protocol to reduce the infection burden in Saudi Arabia could benefit from the implementation of a local antibiogram database in tandem with a national antimicrobial stewardship and infection prevention program.
Topics: Humans; Acinetobacter baumannii; Saudi Arabia; beta-Lactamases; Anti-Bacterial Agents; Carbapenems; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 37582561
DOI: 10.15537/smj.2023.44.8.20230194 -
Cell Reports Oct 2023Acquired drug resistance is a major problem in the treatment of cancer. hTERT-immortalized, untransformed RPE-1 cells can acquire resistance to Taxol by derepressing the...
Acquired drug resistance is a major problem in the treatment of cancer. hTERT-immortalized, untransformed RPE-1 cells can acquire resistance to Taxol by derepressing the ABCB1 gene, encoding for the multidrug transporter P-gP. Here, we investigate how the ABCB1 gene is derepressed. ABCB1 activation is associated with reduced H3K9 trimethylation, increased H3K27 acetylation, and ABCB1 displacement from the nuclear lamina. While altering DNA methylation and H3K27 methylation had no major impact on ABCB1 expression, nor did it promote resistance, disrupting the nuclear lamina component Lamin B Receptor did promote the acquisition of a Taxol-resistant phenotype in a subset of cells. CRISPRa-mediated gene activation supported the notion that lamina dissociation influences ABCB1 derepression. We propose a model in which nuclear lamina dissociation of a repressed gene allows for its activation, implying that deregulation of the 3D genome topology could play an important role in tumor evolution and the acquisition of drug resistance.
Topics: Humans; Drug Resistance, Neoplasm; Paclitaxel; Drug Resistance, Multiple; Neoplasms; DNA Methylation; Cell Line, Tumor
PubMed: 37733591
DOI: 10.1016/j.celrep.2023.113124 -
Emerging Microbes & Infections Dec 2024The multi-drug resistant pathogen has gained global attention as an important clinical challenge. Owing to its ability to survive on surfaces, its capacity for...
The multi-drug resistant pathogen has gained global attention as an important clinical challenge. Owing to its ability to survive on surfaces, its capacity for horizontal gene transfer, and its resistance to front-line antibiotics, has established itself as a successful pathogen. Bacterial conjugation is a central mechanism for pathogen evolution. The epidemic multidrug-resistant ACICU harbours a plasmid encoding a Type IV Secretion System (T4SS) with homology to the F-plasmid, and plasmids with homologous gene clusters have been identified in several sequence types. However the genetic and host strain diversity, global distribution, and functional ability of this group of plasmids is not fully understood. Using systematic analysis, we show that pACICU2 belongs to a group of almost 120 T4SS-encoding plasmids within four different species of and one strain of from human and environmental origin, and globally distributed across 20 countries spanning 4 continents. Genetic diversity was observed both outside and within the T4SS-encoding cluster, and 47% of plasmids harboured resistance determinants, with two plasmids harbouring eleven. Conjugation studies with an extensively drug-resistant (XDR) strain showed that the XDR plasmid could be successfully transferred to a more divergent , and transconjugants exhibited the resistance phenotype of the plasmid. Collectively, this demonstrates that these T4SS-encoding plasmids are globally distributed and more widespread among than previously thought, and that they represent an important potential reservoir for future clinical concern.
Topics: Humans; Type IV Secretion Systems; Escherichia coli; Plasmids; Anti-Bacterial Agents; Acinetobacter baumannii; beta-Lactamases; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 38530969
DOI: 10.1080/22221751.2024.2320929 -
Human Vaccines & Immunotherapeutics Dec 2023The rapid increase in antibiotic resistance presents a dire situation necessitating the need for alternative therapeutic agents. Among the current alternative therapies,... (Review)
Review
The rapid increase in antibiotic resistance presents a dire situation necessitating the need for alternative therapeutic agents. Among the current alternative therapies, phage therapy (PT) is promising. This review extensively summarizes preclinical PT approaches in various models. PT has been evaluated in several recent clinical trials. However, there are still several unanswered concerns due to a lack of appropriate regulation and pharmacokinetic data regarding the application of phages in human therapeutic procedures. In this review, we also presented the current state of PT and considered how animal models can be used to adapt these therapies for humans. The development of realistic solutions to circumvent these constraints is critical for advancing this technology.
Topics: Animals; Humans; Phage Therapy; Bacterial Infections; Bacteriophages; Drug Resistance, Multiple, Bacterial; Models, Animal; Anti-Bacterial Agents
PubMed: 36935353
DOI: 10.1080/21645515.2023.2175519 -
Emerging Infectious Diseases Aug 2023Blood and surveillance cultures from an injured service member from Ukraine grew Acinetobacter baumannii, Klebsiella pneumoniae, Enterococcus faecium, and 3 distinct...
Blood and surveillance cultures from an injured service member from Ukraine grew Acinetobacter baumannii, Klebsiella pneumoniae, Enterococcus faecium, and 3 distinct Pseudomonas aeruginosa strains. Isolates were nonsusceptible to most antibiotics and carried an array of antibiotic resistant genes, including carbapenemases (bla, bla, bla, bla, bla) and 16S methyltransferases (armA and rmtB4).
Topics: Humans; Military Personnel; Ukraine; Microbial Sensitivity Tests; Anti-Bacterial Agents; Bacteria; beta-Lactamases; Acinetobacter baumannii; Drug Resistance, Multiple, Bacterial
PubMed: 37406356
DOI: 10.3201/eid2908.230567