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Bacterial resistance to antibiotics is growing up day by day in both community and hospital setting, with a significant impact on the mortality and morbidity rates and the financial burden that is associated. In the last two decades multi drug resistant microorganisms (both hospital- and community-acquired) challenged the scientific groups into dev...
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Aim: Multiple drug resistant bacteria are serious health problems worldwide, with carbapenem resistant and extended spectrum-β-lactamase (ESBL) producing Enterobacteriaceae classified by Centers for Disease Control and Prevention under the category of "Urgent Threats" and "Serious Threats", respectively. The study characterized Escherichia coli fro...
Citations
... Antibiotic overuse and misuse [1] has driven the emergence of antimicrobial-resistant (AMR) pathogens globally [2]. We are now on the verge of a 'post-antibiotic era' , where simple infections threaten to be untreatable with antimicrobials that once revolutionised modern medicine [3]. ...
... AMR gene acquisition was interrogated using the default parameters of ResFinder v4.0 [10], which is integrated into the ARDaP tool. To reduce false-positive and false-negative hits, the default ResFinder database was further curated to [1] remove loci (bla OXA-395_1_AY306133 , bla OXA-396_1_AY306134 , bla PAO_4_AY083592 , bla PAO_1_AY083595 , bla PAO_3_FJ666073 , bla PAO_2_FJ666065 , and crpP_HM560971) that were consistently identified in antimicrobial-sensitive strains; [2] include additional gene variants identified within the Global Dataset in aminoglycoside AMR-conferring genes aac(6')-Ib, aac(6')-Iia, aac(6')-Ibcr, and aac [3]-IIIa; and [3] expand the substrate range for bla OXA-2_1_DQ112222 and bla OXA-2_2_GQ466184 to include meropenem and imipenem, as per ResFinder recommendations for P. aeruginosa. Furthermore, only AMR genes with 100% similarity and 100% coverage are retained by ARDaP. ...
... For example, 11 strains in the Khaledi et al. dataset [9] possessed variants known to confer ceftazidime AMR (e.g. bla VIM- [2,4,45], bla OXA-2 , bla GES- [1,5]) yet were reported as ceftazidimesensitive, and 22 strains in the Kos et al. dataset were amikacin-sensitive, yet possessed the aminoglycosidemodifying enzyme gene aac(6')-Ib-cr, known to cause amikacin AMR and reduced ciprofloxacin susceptibility [125]. Due to the presence of these known AMR variants, all tools identified these strains as AMR, contributing to imperfect bACC (Fig. 1) and poor precision (Fig. 2) for amikacin and ceftazidime. ...
Background
Antimicrobial resistance (AMR) is an intensifying threat that requires urgent mitigation to avoid a post-antibiotic era. Pseudomonas aeruginosa represents one of the greatest AMR concerns due to increasing multi- and pan-drug resistance rates. Shotgun sequencing is gaining traction for in silico AMR profiling due to its unambiguity and transferability; however, accurate and comprehensive AMR prediction from P. aeruginosa genomes remains an unsolved problem.
Methods
We first curated the most comprehensive database yet of known P. aeruginosa AMR variants. Next, we performed comparative genomics and microbial genome-wide association study analysis across a Global isolate Dataset (n = 1877) with paired antimicrobial phenotype and genomic data to identify novel AMR variants. Finally, the performance of our P. aeruginosa AMR database, implemented in our AMR detection and prediction tool, ARDaP, was compared with three previously published in silico AMR gene detection or phenotype prediction tools—abritAMR, AMRFinderPlus, ResFinder—across both the Global Dataset and an analysis-naïve Validation Dataset (n = 102).
Results
Our AMR database comprises 3639 mobile AMR genes and 728 chromosomal variants, including 75 previously unreported chromosomal AMR variants, 10 variants associated with unusual antimicrobial susceptibility, and 281 chromosomal variants that we show are unlikely to confer AMR. Our pipeline achieved a genotype-phenotype balanced accuracy (bACC) of 85% and 81% across 10 clinically relevant antibiotics when tested against the Global and Validation Datasets, respectively, vs. just 56% and 54% with abritAMR, 58% and 54% with AMRFinderPlus, and 60% and 53% with ResFinder. ARDaP’s superior performance was predominantly due to the inclusion of chromosomal AMR variants, which are generally not identified with most AMR identification tools.
Conclusions
Our ARDaP software and associated AMR variant database provides an accurate tool for predicting AMR phenotypes in P. aeruginosa, far surpassing the performance of current tools. Implementation of ARDaP for routine AMR prediction from P. aeruginosa genomes and metagenomes will improve AMR identification, addressing a critical facet in combatting this treatment-refractory pathogen. However, knowledge gaps remain in our understanding of the P. aeruginosa resistome, particularly the basis of colistin AMR.
... The development of new antimicrobial agents was continuously required due to the risk of the development of drug-resistant bacteria 1,2 . It is predicted that the number of resistant infections caused death will reach 10 million per year by 2050 without the development of novel antimicrobial agents 3 . ...
The utilization of machine learning has a potential to improve the environment of the development of antimicrobial agents. For practical use of machine learning, it is important that the conversion of molecules information to an appropriate descriptor because too informative descriptor requires enormous computation time and experiments for gathering data, whereas a less informative descriptor has problems in validity. In this study, we utilized a descriptor only focused on substituent. The type and the position of substituents on the molecules that have a 4-quinolone structure (11,879 compounds) were converted to the combined substituent number (CSN). While the CSN does not include information on the detailed structure, physical properties, and quantum chemistry of molecules, the prediction model constructed by machine learning of CSN indicated a sufficient coefficient of determination (0.719 for the training dataset and 0.519 for the validation dataset). In addition, this CSN can easily construct the unknown molecules library which has a relatively consistent structure by recombination of substituents (32,079,318 compounds) and screening of them. The validity of the prediction model was also confirmed by growth inhibition experiments for E. coli using the model-suggested molecules and commercially available antimicrobial agents.
... followed by Staphylococcus aureus (n = 53), Campylobacter jejuni (n = 53), Pseudomonas aeruginosa (n = 53), Klebsiella pneumoniae (n = 52) and Acinetobacter baumannii (n = 51). As shown in (Supplemental table 1), four of six "ESKAPE" pathogens [81] were among the top 10 targeted bacteria. Additionally, 11 of 18 urgent and serious bacterial threats listed in the antibiotic resistance threats in the United States report [82] were investigated. ...
... For instance, a study conducted in China reported a high prevalence of carbapenem-resistant K. pneumoniae strains and their association with a higher mortality rate among patients with bloodstream infections [25]. Another study conducted in the USA reported an increase in the incidence of K. pneumoniae infections resistant to carbapenems and colistin, highlighting the urgent need for novel antimicrobial agents to combat these resistant strains [26]. The emergence of carbapenem-resistant K. pneumoniae (CRKP) strains prompt the implementation of infection control measures essential to prevent the spread of beta-lactam resistance in K. pneumoniae and other bacterial pathogens [30]. ...
Antibiotic resistance is a growing concern in healthcare and medicine. This research was carried out to analyze whole genome sequences of Klebsiella pneumoniae ST16 with the goal of identifying genes that cause resistance to antibiotics and find potential bioactive compounds that can inhibit their growth. The study discovered genes that contribute to resistance against types of antibiotics such as macrolides, fluoroquinolones, aminoglycosides, sulphonamides, rifampicin, trimethoprim, and beta-lactams. Notable genes identified include blaTEM 1B, blaCTXM 15, and blaNDM-1. Furthermore, changes were observed in the acrR, ompK36, and gyrA genes, along with
alterations in the corresponding acids, which are associated with resistance. The analysis also examined the alleles at each locus and found that the FIA locus had a new allele. Molecular docking results revealed that baicalein showed docking scores of − 7.7 kcal/mol when binding with New Delhi Metallo 1 (NDM-1) related to beta-lactams. The RMSD plot demonstrated behavior for both Baicalein and Adapalene complexes of NDM-1 over
a 50 ns simulation period. However, the higher Rg value for the drug-protein complex (NDM-1 Beta-Lactamase 1-Adapalene) indicates it may be slightly unstable in interaction compared to our test compound-protein complex (NDM-1 Beta-Lactamase 1-Baicalein). Summarily, the study offers information about how antibiotic resistance works against the NDM-1 gene and its role in beta-lactam resistance based on analysis which reveals that beyond baicalein, other excellent bioactive (taxifolin, and ellagic acid) strongly bind to the NDM 1 domain and can be
further investigated experimentally.
... In addition, ceftolozane is a recent cephalosporin with excellent activity against Pseudomonas that has been regarded as anti-pseudomonal [68]. While the designations of anti-MRSA and antipseudomonal cephalosporins as distinct generations or subclasses of previous generations have yet to be finalized, they reflect important expansions to the cephalosporin antibiotic class [60,69]. The relationship between molecular structure and mechanism of action and/or resistance for cephalosporins will be further discussed in subsequent sections. ...
Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.
... Among the antibiotics administered, tetracyclines have been some of the more common ones in use for therapeutic purposes in the swine industry in the U.S. [9]. Tetracyclines exhibit antimicrobial activity via inhibition of protein synthesis in bacterial cells by attachment to the 30S ribosomal subunit, thus preventing aminoacyl-tRNA binding to the mRNA-ribosome complex [11,12]. Derivatives such as chlortetracycline have been extensively used for growth promotion, but banning the use of tetracyclines as growth promoters in the European Union has not diminished the occurrence of tetracycline resistance in Salmonella from swine [11]. ...
Concern exists that the continued use of antibiotics in animal feeds may lead to an increased prevalence of resistant bacteria within the host animal’s gastrointestinal tract. To evaluate the effect of chlortetracycline on the persistence of Salmonella enterica serotype Typhimurium within a diverse population of porcine cecal bacteria, we cultured a mixed population of cecal bacteria without or with added chlortetracycline. When grown at a 24 h vessel turnover rate, chlortetracycline-susceptible S. Typhimurium exhibited more than 2.5 times faster (p < 0.05) disappearance rates than theoretically expected (0.301 log10 colony-forming unit/mL per day) but did not differ whether treated or not with 55 mg of chlortetracycline/L. Chlortetracycline-resistant S. Typhimurium was not recovered from any of these cultures. When the mixed cultures were inoculated with a chlortetracycline-resistant S. Typhimurium, rates of disappearance were nearly two times slower (p < 0.05) than those observed earlier with chlortetracycline-susceptible S. Typhimurium, and cultures persisted at >2 log10 colony-forming units/mL for up to 14 days of treatment with 110 mg of chlortetracycline/L. Under the conditions of this study, chlortetracycline-resistant S. Typhimurium was competitively enabled to persist longer within the mixed populations of porcine gut bacteria than chlortetracycline-susceptible S. Typhimurium, regardless of the presence or absence of added chlortetracycline.
... The breakdown of the skin barrier is followed by bacterial invasion, which can increase oxidative stress and possibly result in soft tissue necrosis, systemic infection, shock, or death. [1,2] Antibiotics remain the traditional method of clearing these bacterial invasions; however, there is currently no way to avoid the potential of antimicrobial resistance due to the widespread use of antibiotics. [3] Research on novel antimicrobial agents and strategies to combat drug resistance is challenging because of the difficulty in reconciling their adaptability, cost, performance, and safety. ...
Removal of invasive bacteria is critical for proper wound healing. This task is challenging because these bacteria can trigger intense oxidative stress and gradually develop antibiotic resistance. Here, the use of a multienzyme‐integrated nanocatalytic platform is reported for efficient bacterial clearance and mitigation of inflammatory responses, constructed by physically adsorbing natural superoxide dismutase (SOD), in situ reduction of gold nanoparticles (Au NPs), and incorporation of a DNAzyme on 2D NiCoCu metal–organic frameworks (DNAzyme/SOD/Au@NiCoCu MOFs, termed DSAM), which can adapt to infected wounds. O2 and H2O2 replenishment is achieved and alleviated the hypoxic microenvironment using the antioxidant properties of SOD. The H2O2 produced during the reaction is decomposed by peroxidase (POD)‐like activity enhanced by Au NPs and DNAzyme, releasing highly toxic hydroxyl radicals (•OH) to kill the bacteria. In addition, it possesses glutathione peroxidase (GPx)‐like activity, which depletes GSH and prevents •OH loss. Systematic antimicrobial tests are performed against bacteria using this multienzyme‐integrated nanoplatform. A dual‐mode strategy involving natural enzyme‐enhanced antioxidant capacity and artificial enzyme‐enhanced •OH release to develop an efficient and novel enzyme‐integrated therapeutic platform is integrated.
... Furthermore, bacterial species have the inbuilt genetic capacities to express resistance in response to environmental pressure provided by the misuse or overuse of antibiotics and to carry out a horizontal transmission of resistance genes to neighbouring bacterial populations causing the emergence of multi-drug resistance mechanisms for the various antibiotics used against them (D'Costa et al., 2006). The resistance to antibiotics by the targeted bacteria species is growing rapidly in both hospital and community settings, resulting in increased mortality and morbidity rates, prolonged hospital stays and its attendant costs (Biek et al., 2010;Bassetti et al., 2013). The major bacterial species implicated in antibiotic resistance include the so-called 'E.S.K.A.P.E. ...
... Some Enterobacterales can produce hydrolytic enzymes called extended-spectrum betalactamases, which inactivate and destroy most of the commonly used extended-spectrum antibiotics, including penicillins, thirdand fourth-generation cephalosporins, and monobactams, making these drugs ineffective for treating ESBL-associated bacterial infections (3,4). Due to their remarkable safety profiles and broad-spectrum activity against a broad range of pathogens, betalactam antibiotics remain a preferred choice for first-line care (5). However, ESBL-producing bacteria can hydrolyze (inactivate) most beta-lactams except cephamycins and carbacephems (6). ...
Background and objectives
The emergence of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) is causing increased morbidity and mortality around the world as a result of therapeutic failures. ESBL-E are priority pathogens due to their multidrug resistance (MDR). In Northern Cameroon, ESBL-producing bacteria, particularly in urinary tract infections (UTIs), are being increasingly isolated. This study aimed to retrospectively determine the prevalence of multi-drug resistant ESBL strains isolated from UTIs in Northern Cameroon and to evaluate the effectiveness of the ATB UR Gallery of BioMérieux in diagnosing ESBL-E in clinical settings.
Methods
Standard microbiology protocols and statistical tools were utilized to identify ESBL-producing bacteria and characterize their phenotypic susceptibility and resistance profiles in the study population.
Results
Out of the 144 enterobacteria isolates successfully cultured, 59 (41%) were identified as MDR strains. The ATB UR EU gallery identified 33 (23%) multi-drug resistant ESBL-producing strains, while the double synergy test identified 35 strains without disc reconciliation and 38 strains after reconciliation. The most prevalent ESBL-E isolate was Escherichia coli, accounting for 77.1% of the isolates, followed by Klebsiella pneumoniae (20%) and Enterobacter aerogenes (2.9%). Additionally, the study revealed the emergence of Imipenem resistance (5.7%), a critical last-resort antibiotic. However, all ESBL strains were sensitive to Fosfomycin (FSF/FOS), demonstrating its potential as an effective therapeutic option. Moreover, 37% of the ESBL producers exhibited co-resistance to over 20 different antibiotics.
Conclusion
This study provides valuable insights into the prevalence and susceptibility patterns of ESBL-E associated with UTIs in Northern Cameroon. These insights emphasizes the importance of implementing appropriate treatment guidelines and antimicrobial stewardship measures to mitigate the spread and impact of MDR ESBL-producing strains on public health.
... 1,2 However, development of new pharmaceutical agents has not been sufficient to solve this devastating problem. 3,4 Therefore, the importance of optimizing the use of antimicrobial agents has increased over the years. ...
The emergence of multidrug-resistant organisms poses a significant threat to global public health, making the optimization of antimicrobial use crucial. Antimicrobial therapy is often initiated in emergency rooms (ERs) and intensive care units (ICUs), where patients are at high risk of infection. Prompt antimicrobial selection is essential in these facilities, and point-of-care testing can guide the appropriate initial antimicrobial therapy. Gram staining, a quick and inexpensive method, was previously used for point-of-care testing by physicians in the 1980s but was discontinued in 1988 in the United States. However, in Japan, the clinical practice of Gram stain-based antimicrobial therapy by physicians has continued in a limited number of hospitals. Several studies undertaken in Japan have shown that Gram staining carried out by trained physicians can reduce the overuse of broad-spectrum antimicrobial agents in ERs and ICUs without worsening patients' outcomes. Gram stain-based antimicrobial therapy reduced unnecessary use of carbapenems in the ER. Furthermore, Gram staining has been shown to significantly reduce the overuse of broad-spectrum antimicrobials without worsening clinical cure and mortality for patients with ventilator-associated pneumonia in the ICU. The classic technique of Gram staining has regained its usefulness through persistent clinical practice in Japan. It is hoped that Japanese researchers in this field will demonstrate to the world the efficacy of the classic technique of Gram staining in addressing this critical problem. Gram staining carried out by trained physicians could serve as a valuable means of optimizing antimicrobial treatment in ERs and ICUs.
