Biology subjects

Nurjadi, D.

Publications and source records attributed to Nurjadi, D..

5 recordsLinked to original sources

bioRxiv2025

Ribosomal protection as a linezolid resistance mechanism in Mycobacterium abscessus

Mycobacterium abscessus has emerged as a significant pulmonary pathogen characterized by its resistance to most first-line antimycobacterial drugs. Recent investigations have highlighted the clinical efficacy of including the oxazolidinone antibiotic linezolid in M. abscessus combination therapies, despite moderate resistance frequently being observed in patient isolates. Even with the potential usefulness of linezolid, the mechanisms that drive linezolid resistance in M. abscessus remain poorly understood. In several bacterial pathogens, including Mycobacterium tuberculosis, ATP-binding cassette (ABC) family proteins of the F subtype (ABC-F) have been found to confer antibiotic resistance to ribosome-targeting antibiotics, including linezolid. Here, we identified an M. abscessus ABC-F protein, MAB_2736c, that causes specific resistance to antibiotics that bind the 50S ribosomal subunit, including linezolid, macrolides, and chloramphenicol. These results demonstrate that targeting ABC-F proteins could help combat intrinsic resistance to several ribosome-targeting antibiotics in mycobacteria.

microbiology↗

bioRxiv2025

Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope

Antibiotic combination in time and space is a key strategy to combat antimicrobial resistance. The success of such treatment designs requires their robust efficacy across treatment conditions and a pathogens genomic diversity. This study found that an initial treatment with a {beta}-lactam antibiotic causes robust cellular sensitization towards an aminoglycoside antibiotic across the high-risk human pathogen Pseudomonas aeruginosa, including resistant strains. This phenomenon of cellular sensitization, termed negative hysteresis, is modulated by the Cpx envelope stress response system and linked to membrane stress during growth. The increase in efficacy is achieved through a {beta}-lactam induced elevated cellular uptake of the subsequently administered aminoglycoside. Negative hysteresis and the Cpx system are linked in several cases to the expression of synergistic drug interactions, thus enhancing efficacy of antibiotic combinations. Overall, our study identifies the phenomenon of negative hysteresis as a robustly inducible phenotype and thus a unique focus for optimizing antimicrobial therapy.

evolutionary biology↗

bioRxiv2025

Evaluating Seqstant LiveGene Analysis in Real-Time Assessment of Metagenomic Next-Generation Sequencing (mNGS) Data from Respiratory Samples

BackgroundThe detection of pathogens causing infections by conventional diagnostic methods can be challenging and next-generation sequencing (NGS) technology offers a promising alternative method. In this study, we evaluated the performance of real-time metagenomic next-generation sequencing (rt-mNGS) for the detection of pathogens in respiratory samples. MethodWe used rt-mNGS, using the Seqstant LiveGene Analysis platform, on 335 respiratory samples in comparison to conventional culture results. ResultsWe observed an overall good concordance in 71.64% (240/335) of the methods. The rt-mNGS outperformed the gold standard culture in 16.12% (54/335) of the samples, while the culture was superior in detecting the clinically relevant pathogen in 12.24% (41/335) of the samples. The non-inferiority of rt-mNGS was statistically significant ({delta} = 10, = 0.05, 1 - {beta}= 0.8). We also observed that the real-time analysis of NGS data is beneficial in obtaining reliable timely results as the initial report at cycle 46 exhibits a Positive Predictive Value (PPV) of 93.75% at the species-level with a sensitivity of 32.09%. ConclusionOverall, our study showed the non-inferiority of rt-mNGS compared to the standard-of-care microbiology for respiratory samples with statistical significance. Moreover, the rt-mNGS method exhibited superior sensitivity and superior overall performance. It also uniquely detected certain organisms that are typically hard to culture. However, rt-mNGS reported a higher number of false positives and faced limitations in detecting Aspergillus spp. In conclusion, the study highlights the potential of rt-mNGS as a powerful tool in clinical diagnostics of respiratory infections and beyond.

microbiology↗

bioRxiv2024

Delaying cefiderocol resistance development in NDM-producing Enterobacter cloacae complex by combining cefiderocol with aztreonam in vitro.

BackgroundThe rapid development of cefiderocol resistance poses a significant concern, particularly in Enterobacterales that produce New Delhi metallo-{beta}-lactamase (NDM). This study explores the potential of inhibiting the development of cefiderocol resistance by combining cefiderocol with aztreonam. MethodsA resistance induction experiment using 20 clinical isolates was performed to assess the impact of cefiderocol-aztreonam on preventing cefiderocol resistance development at 4x and 10x cefiderocol MIC, with and without aztreonam (2, 4, 8 {micro}g/ml). Additionally, serial passaging with doubling cefiderocol concentrations was performed with and without aztreonam. Whole genome sequencing (WGS) was performed to identify potential genetic factors associated with the phenotype. ResultsAmong the 20 E. cloacae complex isolates, 40% (8/20) exhibited a significant reduction in cefiderocol MIC ([≥]4-fold MIC reduction) in the presence of 4 {micro}g/ml aztreonam. Combining cefiderocol with a fixed concentration of 4 {micro}g/ml aztreonam inhibited cefiderocol resistance development in these eight isolates at an inoculum of 107 cfu/ml. Additional resistance induction experiments through serial passaging indicated a delayed emergence of cefiderocol-resistant clones when cefiderocol was combined with aztreonam. WGS analysis revealed a significant positive association between blaCTX-M-15, blaOXA-1, and other co-localized genes with a substantial MIC reduction for cefiderocol-aztreonam compared to cefiderocol alone. ConclusionOur study suggested that cefiderocol resistance development in NDM-producing E. cloacae complex can be delayed or inhibited by combining cefiderocol with aztreonam, even in the presence of multiple {beta}-lactamase genes. A MIC reduction of at least 4-fold emerges as the most reliable predictor for inhibiting resistance development with this dual {beta}-lactam combination.

microbiology↗

bioRxiv2023

Predicting Decision-Making Time for Diagnosis over NGS Cycles: An Interpretable Machine Learning Approach

MotivationGenome sequencing processes are commonly followed by computational analysis in medical diagnosis. The analyses are generally performed once the sequencing process has finished. However, in time-critical applications, it is crucial to start diagnosis once sufficient evidence has been accumulated. This research aims to define a proof-of-principle for predicting earlier time for decision-making using a machine learning approach. The method is evaluated on Illumina sequencing cycles for pathogen diagnosis. ResultsWe utilized a Long-Short Term Memory (LSTM) approach to make predictions for the early decision-making time in time-critical clinical applications. We modeled the (meta-)information obtained from NGS intermediate cycles to investigate whether there are any changes to expect in the remaining sequencing cycles. We tested our model on different patient datasets, resulting in high accuracy of over 98%, indicating the model is independent of a dataset. Furthermore, we can save several hours of turnaround time by using the early prediction results. We used the SHapley Additive exPlanations (SHAP) framework for the interpretation and assessment of the LSTM classifier. AvailabilityThe source code is available at https://gitlab.com/dacs-hpi/ngs-biclass. ContactBernhard.Renard@hpi.de

bioinformatics↗