Biology subjects

Li, B.

Publications and source records attributed to Li, B..

At least 289 records · Page 16Linked to original sources

bioRxiv2023

Highly multiplexed, image-based pooled screens in primary cells and tissues with PerturbView

Optical pooled screening (OPS) is a highly scalable method for linking image-based phenotypes with cellular perturbations. However, it has thus far been restricted to relatively low-plex phenotypic readouts in cancer cell lines in culture, due to limitations associated with in situ sequencing (ISS) of perturbation barcodes. Here, we developed PerturbView, an OPS technology that leverages in vitro transcription (IVT) to amplify barcodes prior to ISS, enabling screens with highly multiplexed phenotypic readouts across diverse systems, including primary cells and tissues. We demonstrate PerturbView in iPSC-derived neurons, primary immune cells, and tumor tissue sections from animal models. In a screen of immune signaling pathways in primary bone marrow-derived macrophages, PerturbView uncovered both known and novel regulators of NF{kappa}B signaling. Furthermore, we combined PerturbView with spatial transcriptomics in tissue sections from a mouse xenograft model, paving the way to in vivo screens with rich optical and transcriptomic phenotypes. PerturbView broadens the scope of OPS to a wide range of models and applications.

systems biology↗

bioRxiv2023

Identification of a Novel Ferroptosis Inducer with Dual Modulatory Effects on GPX4 Activity and Stability

Ferroptosis is a unique form of intracellular iron-dependent cell death that differs from apoptosis, necrosis, and autophagy. GPX4, an antioxidant defense enzyme, plays a pivotal role as regulator of ferroptosis. Extensive researches suggest that targeting GPX4 holds promise for cancer therapy. However, the current GPX4 inhibitors face challenges due to unfavorable drug-like properties, which hinder their progress in clinical development. In this study, we identified a novel inhibitor called MI-2, demonstrating potent ferroptosis-inducing capacity. Mechanistically, MI-2 effectively inhibits the activity of GPX4 by direct interaction. Furthermore, MI-2 promotes the degradation of GPX4 through its well-established target, MALT1. In multiple cancer models, MI-2 has demonstrated synergistic effects when combined with sorafenib or regorafenib, resulting in enhanced ferroptosis induction. These findings highlight the dual modulatory effects of MI-2 on GPX4 activity and stability, offering a promising starting point for the development of drug-like GPX4 inhibitors with translational potential.

cell biology↗

bioRxiv2023

Association of poultry vaccination with the interspecies transmission and molecular evolution of H5 subtype avian influenza virus

The effectiveness of vaccinating poultry in preventing the transmission of highly pathogenic avian influenza viruses (AIVs) has been questioned for years and its impact on wild birds is uncertain 1-3. Here we reconstruct movements of H5 subtype AIV lineages among vaccinated poultry, unvaccinated poultry, and wild birds, worldwide from 1996 to 2023. We find that lineage transitions among host types are lagged and that movements from wild birds to unvaccinated poultry were more frequent than those from wild birds to vaccinated poultry. However, we also find that the HA gene of the AIV lineage that circulated predominately among Chinese poultry with high vaccination coverage underwent faster evolution and greater nonsynonymous divergence than other lineages. Further, this Chinese poultry lineage contained more codons inferred to be under positive selection, including at known antigenic sites, and its rates of nonsynonymous divergence and adaptative fixation increased after mass poultry vaccination began. Our results indicate that the epidemiological, ecological and evolutionary consequences of widespread AIV vaccination in poultry may be linked in complex ways, and that much work is needed to better understand how such interventions may affect AIV transmission to, within and from wild birds.

evolutionary biology↗

bioRxiv2023

Divergence in herbivore resistance during the invasion of a global plant invader

O_LISuccessful plant invasions are often explained with adaptation to novel environments. However, invasive species often occupy broad niches within their native and introduced ranges, and a true understanding of microevolution during invasion therefore requires broad sampling of ranges, ideally with a knowledge of introduction history. C_LIO_LIWe tested for genetic differentiation in herbivore resistance among 128 introduced (Europe, North America) and native (China, Japan) populations of the invasive Japanese knotweed (Reynoutria japonica) in two common gardens in the native range. C_LIO_LIIn both common gardens we found that resistance traits of introduced populations differed from most Chinese native populations, but not from populations in Japan, the putative sources of introduction. Compared to Chinese populations, introduced European populations had thicker leaves with a lower C:N ratio but higher flavonoids contents. In the native range, variation in herbivore resistance was much more strongly associated with climate of origin than in introduced populations. C_LIO_LIOur results support the idea that founder effects played a key role in the invasion of knotweed into Europe and North America, with introduction of particular resistance phenotypes from Japan. Our study also demonstrates how knowledge of introduction history can avoid drawing wrong conclusions from observed biogeographic divergence. C_LI

ecology↗

bioRxiv2023

Regulation of blood pressure by METTL3 via RUNX1b-eNOS pathway in endothelial cells

BackgroundEndothelial cells regulate vascular tone to control the blood pressure (BP) by producing both relaxing and contracting factors. Previously, we identified methyltransferase-like 3 (METTL3), a primary N6-methyladenosine (m6A) methyltransferase, as a key player in alleviating endothelial atherogenic progression. However, its involvement in BP regulation remains unclear. MethodsTo evaluate the role of METTL3 in vivo, mice with EC specific METTL3 deficiency (EC-Mettl3KO) with or without Ang II infusion were used to create a hypertensive model. Functional and MeRIP sequencing analysis were performed to explore the mechanism of METTL3-mediated hypertension. ResultsWe observed a reduction in endothelial METTL3 activity by Ang II in vitro and in vivo. Endothelial METTL3-deficient mice exhibited higher BP than controls, both before and after Ang II infusion. Through m6A sequencing and functional analysis, we identified m6A modification of various RUNX1 monomers resulted in endothelial dysfunction. Mutations in the 3'UTR region of RUNX1b abolished its luciferase reporter activity, and enhanced eNOS promoter luciferase reporter activity with or without METTL3 overexpression. Overexpression of METTL3 by adeno-associated virus reduced Ang II-induced BP elevation. ConclusionThis study reveals that METTL3 alleviates hypertension through m6A-dependent stabilization of RUNX1b mRNA, leading to upregulation of eNOS, thus underscoring the pivotal role of RNA transcriptomics in the regulation of hypertension.

cell biology↗

bioRxiv2023

A Pose-Informed De-Noising Diffusion Model for Adult Naturalistic EEG Signals

Artifact contamination in EEG (electroencephalogram) signals is a significant problem, especially in naturalistic settings where participants can move freely. This contamination stems from various sources like eye movements, muscle activity, sweat, and electrical interference, whose effects differ greatly from each other. Traditional denoising methods, such as Independent Component Analysis, are limited because they assume a linear relationship between the source of the artifacts and the EEG signals, and often require the dominance of one noise source over others. Moreover, these methods need expert knowledge in EEG analysis and lack an objective standard for evaluation. To overcome these challenges, we propose two innovations: Firstly, we introduce the use of "video-estimated" pose coordinates - the x and y positions of different body points (like wrists, eyes, and ankles) - to assist in the EEG denoising process. Secondly, we present a denoising diffusion model, EEG-DDM, that utilizes both the contaminated EEG signals and these pose coordinates to effectively denoise the EEG. Our findings show that incorporating keypoints (pose coordinates) improves denoising performance and helps maintain cross-spatial dependencies in the data. Additionally, we enhance human interpretability of the process by displaying saliency maps generated by our model, which explain the contributions of these keypoints in the denoising process.

neuroscience↗

bioRxiv2023

NS2B-D55E and NS2B-E65D Variations are Responsible for Differences in NS2B-NS3 Protease Activities Between Japanese Encephalitis Virus Genotype I and III in Fluorogenic Peptide Model

Japanese Encephalitis Virus (JEV) NS2B-NS3 is a protein complex composed of NS3 proteases and a NS2B cofactor. The N-terminal protease domain (180 residues) of NS3 (NS3(pro)) interacts directly with a central 40-amino acid hydrophilic domain of NS2B (NS2B(H)) to form an active serine protease. In this study, the recombinant NS2B(H)-NS3(pro) proteases were prepared in E. coli and used to compare the enzymatic activity between genotype I (GI) and III (GIII) NS2B-NS3 proteases. The GI NS2B(H)-NS3(pro) was able to cleave the sites at internal C, NS2A/NS2B, NS2B/NS3 and NS3/NS4A junctions that were identical to the sites proteolytically processed by GIII NS2B(H)-NS3(pro). Analysis of the enzymatic activity of recombinant NS2B(H)-NS3(pro) proteases using a model of fluorogenic peptide substrate revealed that the proteolytical processing activity of GIII NS2B(H)-NS3(pro) was significantly higher than that of GI NS2B(H)-NS3(pro). There were eight amino acid variations between GI and GIII NS2B(H)-NS3(pro), which may be responsible for the difference in enzymatic activities between GI and GIII proteases. Therefore, recombinant mutants were generated by exchanging NS2B(H) and NS3(pro) domains between GI and GIII NS2B(H)-NS3(pro) and subjected to protease activity analysis. Substitution of NS2B(H) significantly altered the protease activities, as compared to the parental NS2B(H)-NS3(pro), suggesting that NS2B(H) played an essential role in regulation of NS3(pro) protease activity. To further identify the amino acids responsible for the difference in protease activities, multiple substitution mutants including the individual and combined mutations at the variant residue 55 and 65 of NS2B(H) were generated and subjected to protease activity analysis. Replacement of NS2B-55 and NS2B-65 of GI to GIII significantly increased the enzymatic activity of GI NS2B(H)-NS3(pro) protease, whereas mutation of NS2B-55 and NS2B-65 of GIII to GI remarkably reduced the enzymatic activity of GIII NS2B(H)-NS3(pro) protease. Overall, these data demonstrated that NS2B-55 and NS2B-65 variations in hydrophilic domain of NS2B co-contributed to the difference in NS2B(H)-NS3(pro) protease activities between GI and GIII. These observations gain an insight into the role of NS2B in regulation of NS3 protease activities, which is useful for understanding the replication of JEV GI and GIII viruses.

microbiology↗

bioRxiv2023

Molecular Regulation of Invasive Protrusion Formation at the Mammalian Fusogenic Synapse

Invasive membrane protrusions play a central role in a variety of cellular processes. Unlike filopodia, invasive protrusions are mechanically stiff and propelled by branched actin polymerization. However, how branched actin filaments are organized to create finger-like invasive protrusions remains a longstanding question in cell biology. Here, by examining the mammalian fusogenic synapse, where invasive protrusions are generated to promote cell membrane juxtaposition and fusion, we have uncovered the mechanism underlying invasive protrusion formation. We show that two Arp2/3 nucleation promoting factors (NPFs), WAVE and N-WASP, exhibit distinct and complementary localization patterns in the protrusions. While WAVE is at the leading edge, N-WASP is recruited by its interacting protein, WIP, to the shaft of the protrusion. During protrusion growth, new branched actin filaments are polymerized at the periphery of the shaft and crosslinked to preexisting actin bundles by the "pioneer" actin-bundling protein dynamin. The thickened actin bundles are further stabilized by WIP, which functions as a WH2 domain-mediated actin-bundling protein. Disrupting any of these components results in defective protrusions and myoblast fusion in cultured cells and/or in mouse embryos. Thus, our study has revealed the intricate spatiotemporal coordination between two NPFs and two actin-bundling proteins in creating invasive protrusions and has general implications in understanding protrusion formation in many cellular processes beyond cell-cell fusion.

cell biology↗

bioRxiv2023

MitoTracer facilitates the identification of informative mitochondrial mutations for precise lineage reconstruction

Mitochondrial (MT) mutations serve as natural genetic markers for inferring clonal relationships using single cell sequencing data. However, the fundamental challenge of MT mutation-based lineage tracing is automated identification of informative MT mutations. Here, we introduced an open-source computational algorithm called "MitoTracer", which accurately identified clonally informative MT mutations and inferred evolutionary lineage from scRNA-seq or scATAC-seq samples. We benchmarked MitoTracer using the ground-truth experimental lineage sequencing data and demonstrated its superior performance over the existing methods measured by high sensitivity and specificity. MitoTracer is compatible with multiple single cell sequencing platforms. Its application to a cancer evolution dataset revealed the genes related to primary BRAF-inhibitor resistance from scRNA-seq data of BRAF-mutated cancer cells. Overall, our work provided a valuable tool for capturing real informative MT mutations and tracing the lineages among cells. TeaserMitoTracer enables automatically and accurately discover informative mitochondrial mutations for lineage tracing.

bioinformatics↗

bioRxiv2023

A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms and therapeutic targets of aging and age-associated diseases. Here we report a novel mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit driven by p53 and cytoplasmic chromatin fragments (CCF). We show, through activation or inactivation of p53 by genetic and pharmacologic approaches, that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), without affecting cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, and this is reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reversed signatures of aging, including age- and senescence-associated transcriptomic signatures of inflammation and age-associated accumulation of monocytes and macrophages in liver. Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation. This pathway is immunomodulatory in mice and a potential target for healthy aging interventions by small molecules already shown to activate p53.

cell biology↗

bioRxiv2023

Specific and comprehensive genetic targeting reveals brain-wide distribution and synaptic input patterns of GABAergic axo-axonic interneurons

Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex, hippocampus, and basolateral amygdala (BLA). AACs selectively innervate glutamatergic projection neurons (PNs) at their axon initial segment (AIS), thus may exert decisive control over PN spiking and regulate PN functional ensembles. However, the brain-wide distribution, synaptic connectivity, and circuit function of AACs remains poorly understood, largely due to the lack of specific and reliable experimental tools. Here, we have established an intersectional genetic strategy that achieves specific and comprehensive targeting of AACs throughout the mouse brain based on their lineage (Nkx2.1) and molecular (Unc5b, Pthlh) markers. We discovered that AACs are deployed across essentially all the pallium-derived brain structures, including not only the dorsal pallium-derived neocortex and medial pallium-derived hippocampal formation, but also the lateral pallium-derived claustrum-insular complex, and the ventral pallium-derived extended amygdaloid complex and olfactory centers. AACs are also abundant in anterior olfactory nucleus, taenia tecta and lateral septum. AACs show characteristic variations in density across neocortical areas and layers and across subregions of the hippocampal formation. Neocortical AACs comprise multiple laminar subtypes with distinct dendritic and axonal arborization patterns. Retrograde monosynaptic tracing from AACs across neocortical, hippocampal and BLA regions reveal shared as well as distinct patterns of synaptic input. Specific and comprehensive targeting of AACs facilitates the study of their developmental genetic program and circuit function across brain structures, providing a ground truth platform for understanding the conservation and variation of a bona fide cell type across brain regions and species.

neuroscience↗

bioRxiv2023

A Generalized Supervised Contrastive Learning Framework for Integrative Multi-omics Prediction Models

Recent technological advances have highlighted the significant impact of the human microbiome and metabolites on physiological conditions. Integrating microbiome and metabolite data has shown promise in predictive capabilities. We developed a new supervised contrastive learning framework, MB-SupCon-cont, that (1) proposes a general contrastive learning framework for continuous outcomes and (2) improves prediction accuracy over models using single omics data. Simulation studies confirmed the improved performance of MB-SupCon-cont, and applied scenarios in type 2 diabetes and high-fat diet studies also showed improved prediction performance. Overall, MB-SupCon-cont is a versatile research tool for multi-omics prediction models.

bioinformatics↗

bioRxiv2023

Identification and functional analysis of eRNA markers for hepatocellular carcinoma based on high-throughput data

Hepatocellular carcinoma (HCC) is a common type of liver cancer with a high mortality rate. enhancer RNA (eRNA) has been proved to play an important role in cancer progress and development. However, the eRNA studies in HCC are still limited. In this study, we attempted to identify some eRNA biomarkers for HCC diagnosis and analyzed their biological function. First, we identified three eRNA biomarkers (CAP2e, COLEC10e, and MARCOe), which were significant differentially expressed between tumor and normal tissues in 115 HCC patients across three datasets. CAP2e demonstrated upregulation in tumors while COLEC10e and MARCOe were downregulated. These results could be validated in TCGA-LIHC data. There were significant positive correlations between the expression of these eRNAs and their host genes. Then, functional enrichment analysis of protein-coding genes associated with the eRNA biomarkers revealed their involvement in cancer-related pathways. MARCOe was suggested to be a potential target for therapeutic drugs in HCC by a drug related study. The next, survival analysis demonstrated significant prognostic values of these eRNAs in prediction of overall survival. Immune infiltration analysis revealed a positive correlation between MARCOe expression and immune cell infiltration level. Finally, we found similar expression patterns of these eRNA biomarkers in other cancers, such as cholangiocarcinoma, through a pan-cancer comparison. CAP2e and COLEC10e in HCC were validated by other studies. However, the studies about MARCOe in HCC were limited. In conclusion, as best as our knowledge, it is the first time to identify three eRNA biomarkers for HCC diagnosis. These biomarkers are proved to be involved in HCC progress and development, have prognosis prediction values, and are potential to be therapeutic targets.

cancer biology↗

bioRxiv2023

A dipteran parasite regulates 20E synthesis and antibacterial activity of the host for development through inducing host nitric oxide production

Parasites primarily rely on the host to survive, and have evolved diverse survival strategies. In the present study, we report a specific survival strategy of a dipteran parasite Exorista sorbillans (Diptera: Tachinidae), which is a potential biological control agent for agricultural pests and a pest in sericulture. We found that the expression levels of host nitric oxide synthase (NOS) and nitric oxide (NO) production were increased after E. sorbillans infection. Reducing NOS expression and NO production with a NOS inhibitor (L-NAME) in infected hosts significantly impeded the growth of E. sorbillans larvae. Moreover, the 20-hydroxyecdysone (20E) biosynthesis of infected hosts was elevated with increasing NO production, and inhibiting NOS expression also lowered 20E biosynthesis. More importantly, induced NO synthesis was required to eliminate intracellular bacterial pathogens that presumably competed for shared host resources. Inhibiting NOS expression down-regulated the transcription of antimicrobial peptide genes and increased the number of bacteria in infected hosts. Collectively, this study revealed a new perspective on the role of NO in host-parasite interactions and a novel mechanism for parasite regulation of host to support its development. Author summaryParasites are ubiquitous on earth and diverse, and have evolved various strategies to match their own specific requirements for survival within the host. In this study, we found that Exorista sorbillans, an endoparasite of many agricultural pests and the main insect pest in sericulture, used a novel strategy to manipulate its host NO synthesis for survival within its host Bombyx mori. Specifically, NOS expression and the production of NO in the host were up-regulated by E. sorbillans infection, which benefited larval E. sorbillans development. Meanwhile, increased NO production in host activated 20E synthesis of parasitized hosts and triggered the expression of AMPs against the invasion of pathogenic bacteria to avoid nutritional competence in the host. Our study provides innovative insights into the mechanisms by which a parasite manipulates host NO production for development and may help to expand our knowledge of other parasitic systems.

pathology↗

bioRxiv2023

A bioactive peptide from the pearl has dual roles in resisting SARS-CoV-2 infection and its complications

Angiotensin-converting enzyme 2 (ACE2) is a critical receptor for the entry of the SARS-CoV-2 virus into cells. Moreover, a decrease in ACE2 level and its activity due to SARS-CoV-2 infection is considered a crucial reason for the development of Covid-19-associated complications. Here, we report a bioactive peptide derived from the seawater pearl oyster Pinctada fucata, named SCOL polypeptide, which binds strongly to ACE2 and effectively inhibits 65% of the binding of the SARS-CoV-2 S protein to ACE2; thus, this peptide can be used as a blocker to enable cells to resist SARS-CoV-2 infection. The SCOL polypeptide also increases ACE2 enzyme activity by 3.76 times. Previous studies have shown that ACE2 deficiency is associated with inflammation, pain, cardiovascular diseases, insulin resistance, and nervous system injury. Therefore, the SCOL polypeptide can be used to treat or alleviate complications such as lung inflammation, pain, diabetes, cardiovascular diseases, and loss of taste or smell caused by SARS-CoV-2 infection. Thus, the SCOL polypeptide can play a dual role in resisting SARS-CoV-2 infection.

biochemistry↗

bioRxiv2023

Liver regeneration by a population of midzone-located mesenchymal-hepatocyte hybrid cells

Regenerative medicine relies on deep understanding of the mechanisms of organ repair and regeneration. The liver, an organ with critical metabolic functions carried out by hepatocytes located in zones 1-3 of liver lobules, has the capacity to fully regenerate itself, which is mainly attributable to midzone hepatocytes. Yet, how differentiated midzone hepatocytes execute transzone regeneration and quickly recover most of the liver mass remains a myth. Here, we uncover a mesenchymal-hepatocyte population (13.7% of total hepatocytes) that are derived from Twist2-lineage EpCAM+ progenitors, midzone-located, highly polyploidy, and equipped with great mitogenic and migratory capabilities to the detriment of metabolism. They regenerate about 50% of new hepatocytes and repopulate zones 1 and 3 in liver regeneration. Mechanistically, expansion of these cells is negatively controlled by Notch1 signaling. This study has thus uncovered a hepatocyte subpopulation with great proliferation potential and important mechanisms of liver regeneration.

cell biology↗

bioRxiv2023

Structural covariation between cerebellum and cerebral cortex is atypically modulated by thalamus in autism spectrum disorder

Despite its strong interconnectivity with the cerebral cortex, the influence of the human cerebellum on neocortical structure and its role in the development of neuropsychiatric disorders is unclear. Because cerebellar damage in early postnatal life creates a high risk for autism spectrum disorder (ASD), we investigated inter-relationships in cerebello-cerebral morphology. Leveraging a large structural brain MRI dataset in neurotypical children (n=375) and those diagnosed with ASD (n=373), we examined whether volumetric variation in cerebellar structure across individuals was correlated with neocortical variation during development, modeling the thalamus as a moderating coupling factor. We found negative covariation between cerebellar cortical regions and thalamic/sensorimotor neocortical regions, and positive covariation between thalamic and sensorimotor neocortical regions. This pattern aligned with the major disynaptic path of cerebellar inhibition to thalamocortical excitation. Examining the dependence of this structural covariation on ASD diagnosis, we found that neurotypical and ASD children displayed inverted hemispheric biases. In ASD, the thalamus moderated structural associations between the left cerebellum and right sensorimotor cortex. For neurotypical children, right cerebellum and left sensorimotor cortex were coupled. Notably, structural coupling between cerebellum, thalamus, and neocortex was strongest in younger childhood and waned by early adolescence, a time during which behavioral differences were smallest between typically developing and autistic children. In addition to the sensorimotor cortex, cerebellar dentate nuclei in ASD displayed greater coupling to broad neocortical regions, and these nuclei related to cognitive function differently such that greater dentate nuclear volume was associated with greater behavioral impairment in ASD but not in controls. Graph analyses demonstrated that the cerebello-thalamocortical network was more densely and less prolifically interconnected in ASD than in typical development. Taken as a whole, our study reveals a developmental interplay between the cerebellum, thalamus, and neocortex which differs in ASD from neurotypical children. This pattern is consistent with a model of ASD in which early developmental influences of cerebellar output on brain maturation are specifically moderated by cerebello-thalamocortical pathways.

neuroscience↗

bioRxiv2023

KatG catalase deficiency confers bedaquiline hyper-susceptibility to isoniazid resistant Mycobacterium tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) is a growing source of global mortality and threatens global control of tuberculosis (TB) disease. The diarylquinoline bedaquiline (BDQ) recently emerged as a highly efficacious drug against MDR-TB, defined as resistance to the first-line drugs isoniazid (INH) and rifampin. INH resistance is primarily caused by loss-of-function mutations in the catalase KatG, but mechanisms underlying BDQs efficacy against MDR-TB remain unknown. Here we employ a systems biology approach to investigate BDQ hyper-susceptibility in INH-resistant Mycobacterium tuberculosis. We found hyper-susceptibility to BDQ in INH-resistant cells is due to several physiological changes induced by KatG deficiency, including increased susceptibility to reactive oxygen species and DNA damage, remodeling of transcriptional programs, and metabolic repression of folate biosynthesis. We demonstrate BDQ hyper-susceptibility is common in INH-resistant clinical isolates. Collectively, these results highlight how altered bacterial physiology can impact drug efficacy in drug-resistant bacteria.

microbiology↗