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908600.9849Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas. Drug resistant tuberculosis is increasing world-wide. Resistance against isoniazid (INH), rifampicin (RIF), or both (multi-drug resistant TB, MDR-TB) is of particular concern, since INH and RIF form part of the standard regimen for TB disease. While it is known that suboptimal treatment can lead to resistance, it remains unclear how host immune responses and antibiotic dynamics within granulomas (sites of infection) affect emergence and selection of drug-resistant bacteria. We take a systems pharmacology approach to explore resistance dynamics within granulomas. We integrate spatio-temporal host immunity, INH and RIF dynamics, and bacterial dynamics (including fitness costs and compensatory mutations) in a computational framework. We simulate resistance emergence in the absence of treatment, as well as resistance selection during INH and/or RIF treatment. There are four main findings. First, in the absence of treatment, the percentage of granulomas containing resistant bacteria mirrors the non-monotonic bacterial dynamics within granulomas. Second, drug-resistant bacteria are less frequently found in non-replicating states in caseum, compared to drug-sensitive bacteria. Third, due to a steeper dose response curve and faster plasma clearance of INH compared to RIF, INH-resistant bacteria have a stronger influence on treatment outcomes than RIF-resistant bacteria. Finally, under combination therapy with INH and RIF, few MDR bacteria are able to significantly affect treatment outcomes. Overall, our approach allows drug-specific prediction of drug resistance emergence and selection in the complex granuloma context. Since our predictions are based on pre-clinical data, our approach can be implemented relatively early in the treatment development process, thereby enabling pro-active rather than reactive responses to emerging drug resistance for new drugs. Furthermore, this quantitative and drug-specific approach can help identify drug-specific properties that influence resistance and use this information to design treatment regimens that minimize resistance selection and expand the useful life-span of new antibiotics.201829746491
876610.9848Partitioning the Effects of Soil Legacy and Pathogen Exposure Determining Soil Suppressiveness via Induced Systemic Resistance. Beneficial host-associated bacteria can assist plant protection against pathogens. In particular, specific microbes are able to induce plant systemic resistance. However, it remains largely elusive which specific microbial taxa and functions trigger plant immune responses associated with disease suppression. Here, we experimentally studied this by setting up two independent microcosm experiments that differed in the time at which plants were exposed to the pathogen and the soil legacy (i.e., soils with historically suppressive or conducive). Overall, we found soil legacy effects to have a major influence on disease suppression irrespective of the time prior to pathogen exposure. Rhizosphere bacterial communities of tomato plants were significantly different between the two soils, with potential beneficial strains occurring at higher relative abundances in the suppressive soil. Root transcriptome analysis revealed the soil legacy to induce differences in gene expression, most importantly, genes involved in the pathway of phenylpropanoid biosynthesis. Last, we found genes in the phenylpropanoid biosynthesis pathway to correlate with specific microbial taxa, including Gp6, Actinomarinicola, Niastella, Phaeodactylibacter, Longimicrobium, Bythopirellula, Brevundimonas, Ferruginivarius, Kushneria, Methylomarinovum, Pseudolabrys, Sphingobium, Sphingomonas, and Alterococcus. Taken together, our study points to the potential regulation of plant systemic resistance by specific microbial taxa, and the importance of soil legacy on disease incidence and eliciting plant-defense mechanisms.202236365269
919220.9843Antimicrobial peptides: Sustainable application informed by evolutionary constraints. The proliferation and global expansion of multidrug-resistant (MDR) bacteria have deepened the need to develop novel antimicrobials. Antimicrobial peptides (AMPs) are regarded as promising antibacterial agents because of their broad-spectrum antibacterial activity and multifaceted mechanisms of action with non-specific targets. However, if AMPs are to be applied sustainably, knowledge of how they induce resistance in pathogenic bacteria must be mastered to avoid repeating the traditional antibiotic resistance mistakes currently faced. Furthermore, the evolutionary constraints on the acquisition of AMP resistance by microorganisms in the natural environment, such as functional compatibility and fitness trade-offs, inform the translational application of AMPs. Consequently, the shortcut to achieve sustainable utilization of AMPs is to uncover the evolutionary constraints of bacteria on AMP resistance in nature and find the tricks to exploit these constraints, such as applying AMP cocktails to minimize the efficacy of selection for resistance or combining nanomaterials to maximize the costs of AMP resistance. Altogether, this review dissects the benefits, challenges, and opportunities of utilizing AMPs against disease-causing bacteria, and highlights the use of AMP cocktails or nanomaterials to proactively address potential AMP resistance crises in the future.202235752270
826430.9843Anti-CRISPR Phages Cooperate to Overcome CRISPR-Cas Immunity. Some phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here, we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As a consequence, Acr-phages often need to cooperate in order to overcome CRISPR resistance, with a first phage blocking the host CRISPR-Cas immune system to allow a second Acr-phage to successfully replicate. This cooperation leads to epidemiological tipping points in which the initial density of Acr-phage tips the balance from phage extinction to a phage epidemic. Furthermore, both higher levels of CRISPR-Cas immunity and weaker Acr activities shift the tipping points toward higher initial phage densities. Collectively, these data help elucidate how interactions between phage-encoded immune suppressors and the CRISPR systems they target shape bacteria-phage population dynamics.201830033365
879340.9843Enhanced Phytopathogen Biofilm Control in the Soybean Phyllosphere by the Phoresy of Bacteriophages Hitchhiking on Biocontrol Bacteria. Phage-based biocontrol has shown notable advantages in protecting plants against pathogenic bacteria in agricultural settings compared to chemical-based bactericides. However, the efficiency and scope of phage biocontrol of pathogenic bacteria are limited by the intrinsic properties of phages. Here, we investigated pathogen biofilm eradication in the phyllosphere using the phoresy system of hitchhiking phages onto carrier biocontrol bacteria. The phoresy system efficiently removed the pathogen biofilm in the soybean phyllosphere, reducing the total biomass by 58% and phytopathogens by 82% compared to the untreated control. Biofilm eradication tests demonstrated a significant combined beneficial effect (Bliss independence model, CI < 1) as phages improved carrier bacteria colonization by 1.2-fold and carrier bacteria facilitated phage infection by 1.4-fold. Transcriptomic analysis showed that phoresy significantly enhanced motility (e.g., fliC and pilD genes) and energy metabolism (e.g., pgm and pgk genes) of carrier bacteria and suppressed the defense system (e.g., MSH3 and FLS2 genes) and energy metabolism (e.g., petB and petC genes) of pathogens. Metabolomics analysis revealed that the phoresy system stimulated the secretion of beneficial metabolites (e.g., flavonoid and tropane alkaloid) that could enhance stress response and phyllosphere protection in soybeans. Overall, the phoresy of phages hitchhiking on biocontrol bacteria offers a novel and effective strategy for phyllosphere microbiome manipulation and bacterial disease control.202540315344
937450.9842Mathematical modelling of antibiotic interaction on evolution of antibiotic resistance: an analytical approach. BACKGROUND: The emergence and spread of antibiotic-resistant pathogens have led to the exploration of antibiotic combinations to enhance clinical effectiveness and counter resistance development. Synergistic and antagonistic interactions between antibiotics can intensify or diminish the combined therapy's impact. Moreover, these interactions can evolve as bacteria transition from wildtype to mutant (resistant) strains. Experimental studies have shown that the antagonistically interacting antibiotics against wildtype bacteria slow down the evolution of resistance. Interestingly, other studies have shown that antibiotics that interact antagonistically against mutants accelerate resistance. However, it is unclear if the beneficial effect of antagonism in the wildtype bacteria is more critical than the detrimental effect of antagonism in the mutants. This study aims to illuminate the importance of antibiotic interactions against wildtype bacteria and mutants on the deacceleration of antimicrobial resistance. METHODS: To address this, we developed and analyzed a mathematical model that explores the population dynamics of wildtype and mutant bacteria under the influence of interacting antibiotics. The model investigates the relationship between synergistic and antagonistic antibiotic interactions with respect to the growth rate of mutant bacteria acquiring resistance. Stability analysis was conducted for equilibrium points representing bacteria-free conditions, all-mutant scenarios, and coexistence of both types. Numerical simulations corroborated the analytical findings, illustrating the temporal dynamics of wildtype and mutant bacteria under different combination therapies. RESULTS: Our analysis provides analytical clarification and numerical validation that antibiotic interactions against wildtype bacteria exert a more significant effect on reducing the rate of resistance development than interactions against mutants. Specifically, our findings highlight the crucial role of antagonistic antibiotic interactions against wildtype bacteria in slowing the growth rate of resistant mutants. In contrast, antagonistic interactions against mutants only marginally affect resistance evolution and may even accelerate it. CONCLUSION: Our results emphasize the importance of considering the nature of antibiotic interactions against wildtype bacteria rather than mutants when aiming to slow down the acquisition of antibiotic resistance.202438426146
60060.9842Protein aggregation caused by aminoglycoside action is prevented by a hydrogen peroxide scavenger. Protein mistranslation causes growth arrest in bacteria, mitochondrial dysfunction in yeast, and neurodegeneration in mammals. It remains poorly understood how mistranslated proteins cause such cellular defects. Here we demonstrate that streptomycin, a bactericidal aminoglycoside that increases ribosomal mistranslation, induces transient protein aggregation in wild-type Escherichia coli. We further determined the aggregated proteome using label-free quantitative mass spectrometry. To identify genes that reduce cellular mistranslation toxicity, we selected from an overexpression library protein products that increased resistance against streptomycin and kanamycin. The selected proteins were significantly enriched in members of the oxidation-reduction pathway. Overexpressing one of these proteins, alkyl hydroperoxide reductase subunit F (a protein defending bacteria against hydrogen peroxide), but not its inactive mutant suppressed aggregated protein formation upon streptomycin treatment and increased aminoglycoside resistance. This work provides in-depth analyses of an aggregated proteome caused by streptomycin and suggests that cellular defense against hydrogen peroxide lowers the toxicity of mistranslation.201223122414
672870.9842Relationships between Root Pathogen Resistance, Abundance and Expression of Pseudomonas Antimicrobial Genes, and Soil Properties in Representative Swiss Agricultural Soils. Strains of Pseudomonas that produce antimicrobial metabolites and control soilborne plant diseases have often been isolated from soils defined as disease-suppressive, i.e., soils, in which specific plant pathogens are present, but plants show no or reduced disease symptoms. Moreover, it is assumed that pseudomonads producing antimicrobial compounds such as 2,4-diacetylphloroglucinol (DAPG) or phenazines (PHZ) contribute to the specific disease resistance of suppressive soils. However, pseudomonads producing antimicrobial metabolites are also present in soils that are conducive to disease. Currently, it is still unknown whether and to which extent the abundance of antimicrobials-producing pseudomonads is related to the general disease resistance of common agricultural soils. Moreover, virtually nothing is known about the conditions under which pseudomonads express antimicrobial genes in agricultural field soils. We present here results of the first side-by-side comparison of 10 representative Swiss agricultural soils with a cereal-oriented cropping history for (i) the resistance against two soilborne pathogens, (ii) the abundance of Pseudomonas bacteria harboring genes involved in the biosynthesis of the antimicrobials DAPG, PHZ, and pyrrolnitrin on roots of wheat, and (iii) the ability to support the expression of these genes on the roots. Our study revealed that the level of soil disease resistance strongly depends on the type of pathogen, e.g., soils that are highly resistant to Gaeumannomyces tritici often are highly susceptible to Pythium ultimum and vice versa. There was no significant correlation between the disease resistance of the soils, the abundance of Pseudomonas bacteria carrying DAPG, PHZ, and pyrrolnitrin biosynthetic genes, and the ability of the soils to support the expression of the antimicrobial genes. Correlation analyses indicated that certain soil factors such as silt, clay, and some macro- and micronutrients influence both the abundance and the expression of the antimicrobial genes. Taken together, the results of this study suggests that pseudomonads producing DAPG, PHZ, or pyrrolnitrin are present and abundant in Swiss agricultural soils and that the soils support the expression of the respective biosynthetic genes in these bacteria to various degrees. The precise role that these pseudomonads play in the general disease resistance of the investigated agricultural soils remains elusive.201728424714
830180.9841Metabolic disruption impairs ribosomal protein levels, resulting in enhanced aminoglycoside tolerance. Aminoglycoside antibiotics target ribosomes and are effective against a wide range of bacteria. Here, we demonstrated that knockout strains related to energy metabolism in Escherichia coli showed increased tolerance to aminoglycosides during the mid-exponential growth phase. Contrary to expectations, these mutations did not reduce the proton motive force or aminoglycoside uptake, as there were no significant changes in metabolic indicators or intracellular gentamicin levels between wild-type and mutant strains. Our comprehensive proteomics analysis unveiled a noteworthy upregulation of proteins linked to the tricarboxylic acid (TCA) cycle in the mutant strains during the mid-exponential growth phase, suggesting that these strains compensate for the perturbation in their energy metabolism by increasing TCA cycle activity to maintain their membrane potential and ATP levels. Furthermore, our pathway enrichment analysis shed light on local network clusters displaying downregulation across all mutant strains, which were associated with both large and small ribosomal binding proteins, ribosome biogenesis, translation factor activity, and the biosynthesis of ribonucleoside monophosphates. These findings offer a plausible explanation for the observed tolerance of aminoglycosides in the mutant strains. Altogether, this research provides valuable insights into the mechanisms of aminoglycoside tolerance, paving the way for novel strategies to combat such cells.202439093940
860990.9841Nano-biochar regulates phage-host interactions, reducing antibiotic resistance genes in vermicomposting systems. Biochar amendment reshapes microbial community dynamics in vermicomposting, but the mechanism of how phages respond to this anthropogenic intervention and regulate the dissemination of antibiotic resistance genes (ARGs) remains unclear. In this study, we used metagenomics, viromics, and laboratory validation to explore how nano-biochar affects phage-host interactions and ARGs dissemination in vermicomposting. Our results revealed distinct niche-specific phage life strategies. In vermicompost, lytic phages dominated and used a "kill-the-winner" strategy to suppress antibiotic-resistant bacteria (ARB). In contrast, lysogenic phages prevailed in the earthworm gut, adopting a "piggyback-the-winner" strategy that promoted ARGs transduction through mutualistic host interactions. Nano-biochar induced the conversion of lysogenic to lytic phages in the earthworm gut, while concurrently reducing the abundance of lysogenic phages and their encoded auxiliary metabolic genes carried by ARB. This shift disrupted phage-host mutualism and inhibited ARGs transmission via a "phage shunting" mechanism. In vitro validation with batch culture experiments further confirmed that lysogenic phages increased transduction of ARGs in the earthworm gut, while nano-biochar reduced the spread of ARGs by enhancing lysis infectivity. Our study constructs a mechanistic framework linking nano-biochar induced shifts in phage lifestyles that suppress ARG spread, offering insights into phage-host coadaptation and resistance mitigation strategies in organic waste treatment ecosystems.202540838886
8348100.9840Role of RelA-synthesized (p)ppGpp and ROS-induced mutagenesis in de novo acquisition of antibiotic resistance in E. coli. The stringent response of bacteria to starvation and stress also fulfills a role in addressing the threat of antibiotics. Within this stringent response, (p)ppGpp, synthesized by RelA or SpoT, functions as a global alarmone. However, the effect of this (p)ppGpp on resistance development is poorly understood. Here, we show that knockout of relA or rpoS curtails resistance development against bactericidal antibiotics. The emergence of mutated genes associated with starvation and (p)ppGpp, among others, indicates the activation of stringent responses. The growth rate is decreased in ΔrelA-resistant strains due to the reduced ability to synthesize (p)ppGpp and the persistence of deacylated tRNA impeding protein synthesis. Sluggish cellular activity causes decreased production of reactive oxygen species (ROS), thereby reducing oxidative damage, leading to weakened DNA mismatch repair, potentially reducing the generation of mutations. These findings offer new targets for mitigating antibiotic resistance development, potentially achieved through inhibiting (p)ppGpp or ROS synthesis.202438617560
9191110.9840Blunted blades: new CRISPR-derived technologies to dissect microbial multi-drug resistance and biofilm formation. The spread of multi-drug-resistant (MDR) pathogens has rapidly outpaced the development of effective treatments. Diverse resistance mechanisms further limit the effectiveness of our best treatments, including multi-drug regimens and last line-of-defense antimicrobials. Biofilm formation is a powerful component of microbial pathogenesis, providing a scaffold for efficient colonization and shielding against anti-microbials, which further complicates drug resistance studies. Early genetic knockout tools didn't allow the study of essential genes, but clustered regularly interspaced palindromic repeat inference (CRISPRi) technologies have overcome this challenge via genetic silencing. These tools rapidly evolved to meet new demands and exploit native CRISPR systems. Modern tools range from the creation of massive CRISPRi libraries to tunable modulation of gene expression with CRISPR activation (CRISPRa). This review discusses the rapid expansion of CRISPRi/a-based technologies, their use in investigating MDR and biofilm formation, and how this drives further development of a potent tool to comprehensively examine multi-drug resistance.202438511958
8668120.9840Globally Abundant "Candidatus Udaeobacter" Benefits from Release of Antibiotics in Soil and Potentially Performs Trace Gas Scavenging. Verrucomicrobia affiliated with "Candidatus Udaeobacter" belong to the most abundant soil bacteria worldwide. Although the synthesis of antibiotics presumably evolved in soil, and environmental pollution with antimicrobials increases, the impact of these complex molecules on "Ca Udaeobacter" remains to be elucidated. In this study, we demonstrate that "Ca. Udaeobacter" representatives residing in grassland as well as forest soil ecosystems show multidrug resistance and even take advantage of antibiotics release. Soils treated with up to six different antibiotics exhibited a higher "Ca. Udaeobacter" abundance than corresponding controls after 3, 8, and 20 days of incubation. In this context, we provide evidence that "Ca. Udaeobacter" representatives may utilize nutrients which are released due to antibiotic-driven lysis of other soil microbes and thereby reduce energetically expensive synthesis of required biomolecules. Moreover, genomic analysis revealed the presence of genes conferring resistance to multiple classes of antibiotics and indicated that "Ca. Udaeobacter" representatives most likely oxidize the trace gas H(2) to generate energy. This energy might be required for long-term persistence in terrestrial habitats, as already suggested for other dominant soil bacteria. Our study illustrates, for the first time, that globally abundant "Ca. Udaeobacter" benefits from release of antibiotics, which confers advantages over other soil bacteria and represents a so-far overlooked fundamental lifestyle feature of this poorly characterized verrucomicrobial genus. Furthermore, our study suggests that "Ca. Udaeobacter" representatives can utilize H(2) as an alternative electron donor.IMPORTANCE Soil bacteria have been investigated for more than a century, but one of the most dominant terrestrial groups on Earth, "Candidatus Udaeobacter," remains elusive and largely unexplored. Its natural habitat is considered a major reservoir of antibiotics, which directly or indirectly impact phylogenetically diverse microorganisms. Here, we found that "Ca. Udaeobacter" representatives exhibit multidrug resistance and not only evade harmful effects of antimicrobials but even benefit from antibiotic pressure in soil. Therefore, "Ca. Udaeobacter" evidently affects the composition of soil resistomes worldwide and might represent a winner of rising environmental pollution with antimicrobials. In addition, our study indicates that "Ca. Udaeobacter" representatives utilize H(2) and thereby contribute to global hydrogen cycling. The here-reported findings provide insights into elementary lifestyle features of "Ca. Udaeobacter," potentially contributing to its successful global dissemination.202032641424
8769130.9840Transgenic soybean of GsMYB10 shapes rhizosphere microbes to promote resistance to aluminum (Al) toxicity. Plant resistance genes could affect rhizosphere microbiota, which in turn enhanced plant resistance to stresses. Our previous study found that overexpression of the GsMYB10 gene led to enhanced tolerance of soybean plants to aluminum (Al) toxicity. However, whether GsMYB10 gene could regulate rhizosphere microbiota to mitigate Al toxicity remains unclear. Here, we analyzed the rhizosphere microbiomes of HC6 soybean (WT) and transgenic soybean (trans-GsMYB10) at three Al concentrations, and constructed three different synthetic microbial communities (SynComs), including bacterial, fungal and cross-kingdom (bacteria and fungi) SynComs to verify their role in improving Al tolerance of soybean. Trans-GsMYB10 shaped the rhizosphere microbial communities and harbored some beneficial microbes, such as Bacillus, Aspergillus and Talaromyces under Al toxicity. Fungal and cross-kingdom SynComs showed a more effective role than the bacterial one in resistance to Al stress, and these SynComs helped soybean resist Al toxicity via affecting some functional genes that involved cell wall biosynthesis and organic acid transport etc. Overall, this study reveals the mechanism of soybean functional genes regulating the synergistic resistance of rhizosphere microbiota and plants to Al toxicity, and also highlights the possibility of focusing on the rhizobial microbial community as a potential molecular breeding target to produce crops.202337187122
562140.9840Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms. Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.202439039256
8297150.9840Novel RpoS-Dependent Mechanisms Strengthen the Envelope Permeability Barrier during Stationary Phase. Gram-negative bacteria have effective methods of excluding toxic compounds, including a largely impermeable outer membrane (OM) and a range of efflux pumps. Furthermore, when cells become nutrient limited, RpoS enacts a global expression change providing cross-protection against many stresses. Here, we utilized sensitivity to an anionic detergent (sodium dodecyl sulfate [SDS]) to probe changes occurring to the cell's permeability barrier during nutrient limitation. Escherichia coli is resistant to SDS whether cells are actively growing, carbon limited, or nitrogen limited. In actively growing cells, this resistance depends on the AcrAB-TolC efflux pump; however, this pump is not necessary for protection under either carbon-limiting or nitrogen-limiting conditions, suggesting an alternative mechanism(s) of SDS resistance. In carbon-limited cells, RpoS-dependent pathways lessen the permeability of the OM, preventing the necessity for efflux. In nitrogen-limited but not carbon-limited cells, the loss of rpoS can be completely compensated for by the AcrAB-TolC efflux pump. We suggest that this difference simply reflects the fact that nitrogen-limited cells have access to a metabolizable energy (carbon) source that can efficiently power the efflux pump. Using a transposon mutant pool sequencing (Tn-Seq) approach, we identified three genes, sanA, dacA, and yhdP, that are necessary for RpoS-dependent SDS resistance in carbon-limited stationary phase. Using genetic analysis, we determined that these genes are involved in two different envelope-strengthening pathways. These genes have not previously been implicated in stationary-phase stress responses. A third novel RpoS-dependent pathway appears to strengthen the cell's permeability barrier in nitrogen-limited cells. Thus, though cells remain phenotypically SDS resistant, SDS resistance mechanisms differ significantly between growth states. IMPORTANCE: Gram-negative bacteria are intrinsically resistant to detergents and many antibiotics due to synergistic activities of a strong outer membrane (OM) permeability barrier and efflux pumps that capture and expel toxic molecules eluding the barrier. When the bacteria are depleted of an essential nutrient, a program of gene expression providing cross-protection against many stresses is induced. Whether this program alters the OM to further strengthen the barrier is unknown. Here, we identify novel pathways dependent on the master regulator of stationary phase that further strengthen the OM permeability barrier during nutrient limitation, circumventing the need for efflux pumps. Decreased permeability of nutrient-limited cells to toxic compounds has important implications for designing new antibiotics capable of targeting Gram-negative bacteria that may be in a growth-limited state.201727821607
8335160.9839Implementing Optogenetic-Controlled Bacterial Systems in Drosophila melanogaster for Alleviation of Heavy Metal Poisoning. Drosophila melanogaster (fruit fly) is an animal model chassis in biological and genetic research owing to its short life cycle, ease of cultivation, and acceptability to genetic modification. While the D. melanogaster chassis offers valuable insights into drug efficacy, toxicity, and mechanisms, several obvious challenges such as dosage control and drug resistance still limit its utility in pharmacological studies. Our research combines optogenetic control with engineered gut bacteria to facilitate the precise delivery of therapeutic substances in D. melanogaster for biomedical research. We have shown that the engineered bacteria can be orally administered to D. melanogaster to get a stable density of approximately 28,000 CFUs/per fly, leading to no detectable negative effects on the growth of D. melanogaster. In a model of D. melanogaster exposure to heavy metal, these orally administered bacteria uniformly express target genes under green light control to produce MtnB protein for binding and detoxifying lead, which significantly reduces the level of oxidative stress in the intestinal tract of Pb-treated flies. This pioneering study lays the groundwork for using optogenetic-controlled bacteria in the model chassis D. melanogaster to advance biomedical applications.202439312764
9736170.9839Coevolutionary phage training leads to greater bacterial suppression and delays the evolution of phage resistance. The evolution of antibiotic-resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria's capacity to evolve resistance may debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many suggest leveraging phages' ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that in vitro, λtrn, a phage trained for 28 d, suppressed bacteria ∼1,000-fold for three to eight times longer than its untrained ancestor. Prolonged suppression was due to a delay in the evolution of resistance caused by several factors. Mutations that confer resistance to λtrn are ∼100× less common, and while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to λtrn. Mutations that confer resistance to λtrn are more costly than mutations for untrained phage resistance. Furthermore, when resistance does evolve, λtrn is better able to suppress these forms of resistance. One way that λtrn improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This transfer of information from the host genome is an unexpected but highly efficient mode of training phage. Lastly, we found that many other independently trained λ phages were able to suppress bacterial populations, supporting the important role training could play during phage therapeutic development.202134083444
8361180.9839Functional potential and evolutionary response to long-term heat selection of bacterial associates of coral photosymbionts. Symbiotic microorganisms are crucial for the survival of corals and their resistance to coral bleaching in the face of climate change. However, the impact of microbe-microbe interactions on coral functioning is mostly unknown but could be essential factors for coral adaption to future climates. Here, we investigated interactions between cultured dinoflagellates of the Symbiodiniaceae family, essential photosymbionts of corals, and associated bacteria. By assessing the genomic potential of 49 bacteria, we found that they are likely beneficial for Symbiodiniaceae, through the production of B vitamins and antioxidants. Additionally, bacterial genes involved in host-symbiont interactions, such as secretion systems, accumulated mutations following long-term exposure to heat, suggesting symbiotic interactions may change under climate change. This highlights the importance of microbe-microbe interactions in coral functioning.202337909753
9372190.9839The population genetics of collateral resistance and sensitivity. Resistance mutations against one drug can elicit collateral sensitivity against other drugs. Multi-drug treatments exploiting such trade-offs can help slow down the evolution of resistance. However, if mutations with diverse collateral effects are available, a treated population may evolve either collateral sensitivity or collateral resistance. How to design treatments robust to such uncertainty is unclear. We show that many resistance mutations in Escherichia coli against various antibiotics indeed have diverse collateral effects. We propose to characterize such diversity with a joint distribution of fitness effects (JDFE) and develop a theory for describing and predicting collateral evolution based on simple statistics of the JDFE. We show how to robustly rank drug pairs to minimize the risk of collateral resistance and how to estimate JDFEs. In addition to practical applications, these results have implications for our understanding of evolution in variable environments.202134889185