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MSystems Jun 2024Relationships between bacterial taxa are traditionally defined using 16S rRNA nucleotide similarity or average nucleotide identity. Improvements in sequencing technology...
UNLABELLED
Relationships between bacterial taxa are traditionally defined using 16S rRNA nucleotide similarity or average nucleotide identity. Improvements in sequencing technology provide additional pairwise information on genome sequences, which may provide valuable information on genomic relationships. Mapping orthologous gene locations between genome pairs, known as synteny, is typically implemented in the discovery of new species and has not been systematically applied to bacterial genomes. Using a data set of 378 bacterial genomes, we developed and tested a new measure of synteny similarity between a pair of genomes, which was scaled onto 16S rRNA distance using covariance matrices. Based on the input gene functions used (i.e., core, antibiotic resistance, and virulence), we observed varying topological arrangements of bacterial relationship networks by applying (i) complete linkage hierarchical clustering and (ii) K-nearest neighbor graph structures to synteny-scaled 16S data. Our metric improved clustering quality comparatively to state-of-the-art average nucleotide identity metrics while preserving clustering assignments for the highest similarity relationships. Our findings indicate that syntenic relationships provide more granular and interpretable relationships for within-genera taxa compared to pairwise similarity measures, particularly in functional contexts.
IMPORTANCE
Given the prevalence and necessity of the 16S rRNA measure in bacterial identification and analysis, this additional analysis adds a functional and synteny-based layer to the identification of relatives and clustering of bacteria genomes. It is also of computational interest to model the bacterial genome as a graph structure, which presents new avenues of genomic analysis for bacteria and their closely related strains and species.
PubMed: 38940518
DOI: 10.1128/msystems.00497-24 -
MSphere Jun 2024Bacterial conjugation systems pose a major threat to human health through their widespread dissemination of mobile genetic elements (MGEs) carrying cargoes of antibiotic...
UNLABELLED
Bacterial conjugation systems pose a major threat to human health through their widespread dissemination of mobile genetic elements (MGEs) carrying cargoes of antibiotic resistance genes. Using the Cre Recombinase Assay for Translocation (CRAfT), we recently reported that the IncFV pED208 conjugation system also translocates at least 16 plasmid-encoded proteins to recipient bacteria. Here, we deployed a high-throughput CRAfT screen to identify the repertoire of chromosomally encoded protein substrates of the pED208 system. We identified 32 substrates encoded by the W3110 genome with functions associated with (i) DNA/nucleotide metabolism, (ii) stress tolerance/physiology, (iii) transcriptional regulation, or (iv) toxin inhibition. The respective gene deletions did not impact pED208 transfer proficiencies, nor did Group 1 (DNA/nucleotide metabolism) mutations detectably alter the SOS response elicited in new transconjugants upon acquisition of pED208. However, MC4100(pED208) donor cells intrinsically exhibit significantly higher SOS activation than plasmid-free MC4100 cells, and this plasmid carriage-induced stress response is further elevated in donor cells deleted of several Group 1 genes. Among 10 characterized substrates, we gained evidence of C-terminal or internal translocation signals that could function independently or synergistically for optimal protein transfer. Remarkably, nearly all tested proteins were also translocated through the IncN pKM101 and IncP RP4 conjugation systems. This repertoire of protein substrates, here termed the F plasmid "conjutome," is thus characterized by functions of potential benefit to new transconjugants, diverse TSs, and the capacity for promiscuous transfer through heterologous conjugation systems.
IMPORTANCE
Conjugation systems comprise a major subfamily of the type IV secretion systems (T4SSs) and are the progenitors of a second large T4SS subfamily dedicated to translocation of protein effectors. This study examined the capacity of conjugation machines to function as protein translocators. Using a high-throughput reporter screen, we determined that 32 chromosomally encoded proteins are delivered through an F plasmid conjugation system. The translocated proteins potentially enhance the establishment of the co-transferred F plasmid or mitigate mating-induced stresses. Translocation signals located C-terminally or internally conferred substrate recognition by the F system and, remarkably, many substrates also were translocated through heterologous conjugation systems. Our findings highlight the plasticity of conjugation systems in their capacities to co-translocate DNA and many protein substrates.
PubMed: 38940509
DOI: 10.1128/msphere.00354-24 -
MSphere Jun 2024is an enteric pathogen that can cause a range of illnesses from mild diarrhea to pseudomembranous colitis and even death. This pathogen often takes advantage of...
UNLABELLED
is an enteric pathogen that can cause a range of illnesses from mild diarrhea to pseudomembranous colitis and even death. This pathogen often takes advantage of microbial dysbiosis provoked by antibiotic use. With the increasing incidence and severity of infections, coupled with high recurrence rates, there is an urgent need to identify innovative therapies that can preserve the healthy state of the gut microbiota. In this study, we screened a microbial metabolite library against . From a collection of 527 metabolites, we identified 18 compounds with no previously identified antimicrobial activity and metabolites that exhibited potent activity against growth. Of these 18 hits, five drugs and three metabolites displayed the most potent anti-. activity and were subsequently assessed against 20 clinical isolates of . These potent agents included ecteinascidin 770 (minimum inhibitory concentration against 50% of isolates [MIC] ≤0.06 µg/mL); 8-hydroxyquinoline derivatives, such as broxyquinoline and choloroquinaldol (MIC = 0.125 µg/mL); ionomycin calcium salt, carbadox, and robenidine hydrochloride (MIC = 1 µg/mL); and dronedarone and milbemycin oxime (MIC = 4 µg/mL). Unlike vancomycin and fidaxomicin, which are the standard-of-care anti-. antibiotics, most of these metabolites showed robust bactericidal activity within 2-8 h with minimal impact on the growth of representative members of the normal gut microbiota. These results suggest that the drugs and microbial metabolite scaffolds may offer alternative avenues to address unmet needs in disease prevention and treatment.
IMPORTANCE
The most frequent infection associated with hospital settings is , which can cause fatal diarrhea and severe colitis, toxic megacolon, sepsis, and leaky gut. Those who have taken antibiotics for other illnesses that affect the gut's healthy microbiota are more susceptible to infection (CDI). Recently, some reports showed higher recurrence rates and resistance to anti-, which may compromise the efficacy of CDI treatment. Our study is significant because it is anticipated to discover novel microbial metabolites and drugs with microbial origins that are safe for the intestinal flora, effective against , and reduce the risk of recurrence associated with CDI.
PubMed: 38940508
DOI: 10.1128/msphere.00273-24 -
Bioinformatics (Oxford, England) Jun 2024World Health Organization estimates that there were over 10 million cases of tuberculosis (TB) worldwide in 2019, resulting in over 1.4 million deaths, with a worrisome...
MOTIVATION
World Health Organization estimates that there were over 10 million cases of tuberculosis (TB) worldwide in 2019, resulting in over 1.4 million deaths, with a worrisome increasing trend yearly. The disease is caused by Mycobacterium tuberculosis (MTB) through airborne transmission. Treatment of TB is estimated to be 85% successful, however, this drops to 57% if MTB exhibits multiple antimicrobial resistance (AMR), for which fewer treatment options are available.
RESULTS
We develop a robust machine-learning classifier using both linear and nonlinear models (i.e. LASSO logistic regression (LR) and random forests (RF)) to predict the phenotypic resistance of Mycobacterium tuberculosis (MTB) for a broad range of antibiotic drugs. We use data from the CRyPTIC consortium to train our classifier, which consists of whole genome sequencing and antibiotic susceptibility testing (AST) phenotypic data for 13 different antibiotics. To train our model, we assemble the sequence data into genomic contigs, identify all unique 31-mers in the set of contigs, and build a feature matrix M, where M[i, j] is equal to the number of times the ith 31-mer occurs in the jth genome. Due to the size of this feature matrix (over 350 million unique 31-mers), we build and use a sparse matrix representation. Our method, which we refer to as MTB++, leverages compact data structures and iterative methods to allow for the screening of all the 31-mers in the development of both LASSO LR and RF. MTB++ is able to achieve high discrimination (F-1 >80%) for the first-line antibiotics. Moreover, MTB++ had the highest F-1 score in all but three classes and was the most comprehensive since it had an F-1 score >75% in all but four (rare) antibiotic drugs. We use our feature selection to contextualize the 31-mers that are used for the prediction of phenotypic resistance, leading to some insights about sequence similarity to genes in MEGARes. Lastly, we give an estimate of the amount of data that is needed in order to provide accurate predictions.
AVAILABILITY
The models and source code are publicly available on Github at https://github.com/M-Serajian/MTB-Pipeline.
Topics: Mycobacterium tuberculosis; Machine Learning; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Anti-Bacterial Agents; Whole Genome Sequencing; Genome, Bacterial; Humans
PubMed: 38940175
DOI: 10.1093/bioinformatics/btae243 -
Annals of Agricultural and... Jun 2024Escherichia coli is one of the most common bacteria isolated from urine samples collected from dogs and cats with urinary tract infection (UTI). Uncomplicated UTIs in...
INTRODUCTION AND OBJECTIVE
Escherichia coli is one of the most common bacteria isolated from urine samples collected from dogs and cats with urinary tract infection (UTI). Uncomplicated UTIs in dogs and cats can be treated with short courses of first-line antimicrobial drugs, e.g. amoxicillin, amoxicillin with clavulanic acid, or trimethoprim/sulfonamide. Recurrent or complicated UTIs often require long-term treatment with broad-spectrum antibiotics. However, the choice of drug should be based on antimicrobial susceptibility.
MATERIAL AND METHODS
Between March - September 2022, E. coli isolates cultured from the urine of 66 dogs and 41 cats with UTI symptoms were tested for antimicrobial resistance by using Minimum Inhibitory Concentration (MIC). Antimicrobial susceptibility was tested for ampicillin, ampicillin/sulbactam, cefazolin, cefuroxime, aztreonam, gentamycin, amikacin, colistin, trimethoprim/sulfamethoxazole, ciprofloxacin, chloramphenicol and tetracycline.
RESULTS
The highest prevalence of resistance was documented for ampicillin (68% in dogs, 100% in cats) and ampicillin with sulbactam (59% in dogs, 54% in cats). The most common antimicrobial resistance patterns of E. coli were ampicillin alone (12 isolates, 29.3% in cats) and beta-lactams, including aztreonam (14 isolates, 21.2% in dogs).
CONCLUSIONS
High resistance to aztreonam (61% and 32% of isolates from dogs and cats, respectively), other beta-lactams, and fluoroquinolones should cause be alarm due to zoonotic potential and cross-transmission of antimicrobial-resistant microorganisms between animals and humans.
Topics: Dogs; Cats; Animals; Urinary Tract Infections; Cat Diseases; Escherichia coli; Dog Diseases; Anti-Bacterial Agents; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial; Escherichia coli Infections; Urinary Bladder; Female; Male
PubMed: 38940100
DOI: 10.26444/aaem/176843 -
Euro Surveillance : Bulletin Europeen... Jun 2024In 2022, an outbreak with severe bloodstream infections caused by occurred in an adult intensive care unit (ICU) in Hungary. Eight cases, five of whom died, were...
In 2022, an outbreak with severe bloodstream infections caused by occurred in an adult intensive care unit (ICU) in Hungary. Eight cases, five of whom died, were detected. Initial control measures could not stop the outbreak. We conducted a matched case-control study. In univariable analysis, the cases were more likely to be located around one sink in the ICU and had more medical procedures and medications than the controls, however, the multivariable analysis was not conclusive. Isolates from blood cultures of the cases and the ICU environment were closely related by whole genome sequencing and resistant or tolerant against the quaternary ammonium compound surface disinfectant used in the ICU. Thus, was able to survive in the environment despite regular cleaning and disinfection. The hospital replaced the disinfectant with another one, tightened the cleaning protocol and strengthened hand hygiene compliance among the healthcare workers. Together, these control measures have proved effective to prevent new cases. Our results highlight the importance of multidisciplinary outbreak investigations, including environmental sampling, molecular typing and testing for disinfectant resistance.
Topics: Humans; Serratia marcescens; Disease Outbreaks; Cross Infection; Hungary; Intensive Care Units; Serratia Infections; Disinfectants; Case-Control Studies; Male; Female; Adult; Middle Aged; Whole Genome Sequencing; Disinfection; Aged; Infection Control; Drug Resistance, Bacterial
PubMed: 38940004
DOI: 10.2807/1560-7917.ES.2024.29.26.2300492 -
Health Care Science Apr 2024This study aimed to assess the role of community pharmacists and their perception toward antimicrobial stewardship, in addition to identifying factors influencing their...
BACKGROUND
This study aimed to assess the role of community pharmacists and their perception toward antimicrobial stewardship, in addition to identifying factors influencing their perception and practices in community pharmacy.
METHODS
A cross-sectional study was carried out among community pharmacists regarding antimicrobial stewardship. Convenience sampling was used to obtain the required sample from a community pharmacy in Baghdad. In total, 381 participants have completed the survey.
RESULTS
The majority of the participants (85.6%) strongly agreed/agreed that "antimicrobial stewardship programs reduce the problems of antibiotic resistance"; and 85.5% of them strongly agreed/agreed that community pharmacists required adequate training on antibiotics use. In addition, high percent of community pharmacists (88.4%) strongly agreed/agreed that pharmacists have a responsibility to take a prominent role in antimicrobial stewardship programs and infection-control programs in the health system. The total score of perception was significantly influenced by older age groups, postgraduate degrees, and experience of 6-10 years ( < 0.001). This study also showed that 65.4% of pharmacists always/often advise patients to continue the full course of antimicrobials, and 64.9% of them reported always/often considering clinical and safety parameters before dispensing antibiotics. The role of pharmacists was significantly influenced by the younger age group, females, higher degree in pharmacy, experience of 3-5 years, and medical complex pharmacy ( < 0.001).
CONCLUSION
Community pharmacists have a good perception toward antimicrobial stewardship programs, but their role is still limited. More efforts are needed to design better strategies for antimicrobial stewardship in community pharmacy.
PubMed: 38939617
DOI: 10.1002/hcs2.92 -
Acta Medica Philippina 2024Based on the 2017-2020 annual report of the Department of Health-Antimicrobial Resistance Surveillance Program, significant resistance patterns have been observed for...
BACKGROUND
Based on the 2017-2020 annual report of the Department of Health-Antimicrobial Resistance Surveillance Program, significant resistance patterns have been observed for common disease-causing pathogens. In the hospital setting, antimicrobial stewardship programs have been implemented to optimize the use of antimicrobials. Drug utilization review studies provide essential feedback to improve prescribing and use of medications.
OBJECTIVES
This study aimed to review drug utilization of monitored parenteral antimicrobials among patients admitted from January to December 2019.
METHODS
The study employed a retrospective, cross-sectional, descriptive research design. A retrospective chart review of drugs administered to patients was conducted.
RESULTS
A total of 821 patients charts met the inclusion criteria. The patients' ages ranged from 18 to 98 years old and 52% were females. General Internal Medicine practitioners (28%) were the top prescribers of monitored parenteral antimicrobials primarily for the management of moderate-risk community-acquired pneumonia (39%). They were mostly indicated for empirical treatment of infections (94%) and were given for an average of 5.73 days.Only 58% of the total cases had orders for culture and sensitivity testing. Of which, principally 47% had colony cultures. Blood (29%) and sputum (27%) were the most common specimens taken for culture and sensitivity testing. The microorganisms often isolated were (19%), (18%), and (9%). In addition, extended-spectrum beta lactamase-producing gram-negative pathogens (4%) and methicillin-resistant (1%) were also isolated. All the microorganisms isolated showed most resistance to ampicillin (81%) and most susceptibility to colistin (100%). There were drug therapy-related problems encountered. There was one case of an adverse drug reaction (0.1%) and two cases of contraindications (0.2%). Therapeutic duplication was also observed in 5% of the cases. Moreover, 39% had instances of drug-drug interactions.Piperacillin-tazobactam had the highest consumption (79.50 defined daily doses/1,000-patient days) among the monitored parenteral antimicrobials.Some prescriptions were deemed inappropriate upon evaluation. 12% of cases were inappropriate based on the justification indicator. As for the critical indicators, duration of therapy (78%) was the main reason. Only four components of the DUE criteria indicators have met or exceeded the established threshold level.The cost analysis indicated that the total actual cost of therapy with the monitored parenteral antimicrobials amounted to ₱17,645,601.73. Considering Department of Health National Antibiotic Guidelines recommendations, ideal total cost of treatment was ₱14,917,214.29. Potential cumulative cost savings of ₱2,728,387.44 could have been achieved for patients admitted last 2019.
CONCLUSION
Consumption of piperacillin-tazobactam was relatively high as compared to the other monitored parenteral antimicrobials covered in this study. Physicians at the study site seldom prescribe monitored parenteral antimicrobials as recommended by the National Antibiotic Guidelines. This is evidenced in the incidence of inappropriate therapy regimens, with inapt duration of therapy as the leading explanation.From the patient's perspective, the main economic implication was on the direct medical costs, particularly the increased cost of the actual antimicrobial therapy prescribed to manage various infections. Adherence of physicians to the established guidelines and selection of the most cost-effective therapy could have resulted in considerable cost savings.
PubMed: 38939423
DOI: 10.47895/amp.vi0.7249 -
Frontiers in Microbiology 2024This study explores the prevalence of adherent-invasive (AIEC) in colorectal cancer (CRC) patients and investigates the potential of effective intracellular antibiotics...
This study explores the prevalence of adherent-invasive (AIEC) in colorectal cancer (CRC) patients and investigates the potential of effective intracellular antibiotics as a therapeutic strategy for CRC patients with AIEC infections. Considering the pivotal role of integrons in bacterial antibiotic resistance, the frequency of class 1 and 2 integrons in AIEC isolated from CRC patients, in one of the referenced 3 gastroenterology clinics in Isfahan, Iran was examined. AIEC strains were isolated from the colorectal biopsies and their antimicrobial sensitivity was assessed using the disc diffusion method. Polymerase chain reaction (PCR) was employed to detect and . The multilocus sequence typing (MLST) method was utilized to type 10 selected isolates. Of the 150 samples, 24 were identified as AIEC, with the highest number isolated from CRC2 (33.4%) and CRC1 (29.16%), and the least from the FH group (8.3%) and control group (12.5%). in 79.2% and in 45.8% of AIEC strains were found and 41.6% of strains had both integrons. AIEC isolates with int1 exhibited the highest sensitivity to trimethoprim-sulfamethoxazole (57.9%), while those with int2 showed the highest sensitivity to ciprofloxacin (63.6%). A significant association between resistance to rifampin and integron 2 presence in AIEC isolates was observed. Furthermore, a significant correlation between integron 1 presence, invasion, survival, and replication within macrophages in AIEC strains was identified. MLST analysis revealed ST131 from CC131 with integron 1 as the most common sequence type (ST). The emergence of such strains in CRC populations poses a serious public health threat. The distribution pattern of STs varied among studied groups, with pandemic STs highlighting the importance of examining and treating patients infected with these isolates. Comprehensive prospective clinical investigations are warranted to assess the prognostic value of detecting this pathovar in CRC and to evaluate therapeutic techniques targeting drug-resistant AIECs, such as phage therapy, bacteriocins, and anti-adhesion compounds, for CRC prevention and treatment.
PubMed: 38939191
DOI: 10.3389/fmicb.2024.1366719 -
Chemical Science Jun 2024Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There...
Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant ; however, understanding of the structure-activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in . This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.
PubMed: 38939155
DOI: 10.1039/d4sc00995a