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843300.9823Thermoresponsive Nanostructures: From Mechano-Bactericidal Action to Bacteria Release. Overuse of antibiotics can increase the risk of notorious antibiotic resistance in bacteria, which has become a growing public health concern worldwide. Featured with the merit of mechanical rupture of bacterial cells, the bioinspired nanopillars are promising alternatives to antibiotics for combating bacterial infections while avoiding antibacterial resistance. However, the resident dead bacterial cells on nanopillars may greatly impair their bactericidal capability and ultimately impede their translational potential toward long-term applications. Here, we show that the functions of bactericidal nanopillars can be significantly broadened by developing a hybrid thermoresponsive polymer@nanopillar-structured surface, which retains all of the attributes of pristine nanopillars and adds one more: releasing dead bacteria. We fabricate this surface through coaxially decorating mechano-bactericidal ZnO nanopillars with thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) brushes. Combining the benefits of ZnO nanopillars and PNIPAAm chains, the antibacterial performances can be controllably regulated between ultrarobust mechano-bactericidal action (∼99%) and remarkable bacteria-releasing efficiency (∼98%). Notably, both the mechanical sterilization against the live bacteria and the controllable release for the pinned dead bacteria solely stem from physical actions, stimulating the exploration of intelligent structure-based bactericidal surfaces with persistent antibacterial properties without the risk of triggering drug resistance.202134905683
873510.9810The Effect of Ice-Nucleation-Active Bacteria on Metabolic Regulation in Evergestis extimalis (Scopoli) (Lepidoptera: Pyralidae) Overwintering Larvae on the Qinghai-Tibet Plateau. Evergestis extimalis (Scopoli) is a significant pest of spring oilseed rape in the Qinghai-Tibet Plateau. It has developed resistance to many commonly used insecticides. Therefore, biopesticides should be used to replace the chemical pesticides in pest control. In this study, the effects of ice-nucleation-active (INA) microbes (Pseudomonas syringae 1.7277, P. syringae 1.3200, and Erwinia pyrifoliae 1.3333) on E. extimalis were evaluated. The supercooling points (SCP) were markedly increased due to the INA bacteria application when they were compared to those of the untreated samples. Specifically, the SCP of E. extimalis after its exposure to a high concentration of INA bacteria in February were -10.72 °C, -13.73 °C, and -14.04 °C. Our findings have demonstrated that the trehalase (Tre) genes were up-regulated by the application of the INA bacteria, thereby resulting in an increased trehalase activity. Overall, the INA bacteria could act as effective heterogeneous ice nuclei which could lower the hardiness of E. extimalis to the cold and then freeze them to death in an extremely cold winter. Therefore, the control of insect pests with INA bacteria goes without doubt, in theory.202236292857
906020.9810Targetable nano-delivery vehicles to deliver anti-bacterial small acid-soluble spore protein (SASP) genes. Interest in phage-based therapeutics is increasing, at least in part due to the need for new treatment options for infections caused by antibiotic-resistant bacteria. It is possible to use wild-type (WT) phages to treat bacterial infections, but it is also possible to modify WT phages to generate therapeutics with improved features. Here, we will discuss features of Phico Therapeutics' SASPject technology, which modifies phages for use as targetable nano-delivery vehicles (NDV), to introduce antibacterial Small Acid Soluble Spore Protein (SASP) genes into specific target bacteria.202134723318
905530.9808siRNA-AGO2 complex inhibits bacterial gene translation: A promising therapeutic strategy for superbug infection. Silencing resistance genes of pathogenic bacteria by RNA interference (RNAi) is a potential strategy to fight antibiotic-resistant bacterial infections. Currently, RNAi cannot be achieved in bacteria due to the lack of RNA-induced silencing complex machinery and the difficulty of small interfering RNA (siRNA) delivery. Here, we show that exosomal siRNAs can be efficiently delivered into bacterial cells and can silence target genes primarily through translational repression without mRNA degradation. The exosomal Argonaute 2 (AGO2) protein forms a complex with siRNAs, which is essential for bacterial gene silencing. Both in vitro and in vivo-generated exosome-packaged siRNAs resensitize methicillin-resistant Staphylococcus aureus (MRSA) to methicillin treatment by silencing the mecA gene, which is the primary beta-lactam resistance determinant of MRSA. This approach significantly enhances the therapeutic effect in a mouse model of MRSA infection. In summary, our study provides a method for siRNA delivery to bacteria that may facilitate the treatment of antibiotic-resistant bacterial infection.202540054457
922240.9806Bacterial proton motive force as an unprecedented target to control antimicrobial resistance. Novel antibacterial therapies are urgently required to tackle the increasing number of multidrug-resistant pathogens. Identification of new antimicrobial targets is critical to avoid possible cross-resistance issues. Bacterial proton motive force (PMF), an energetic pathway located on the bacterial membrane, crucially regulates various biological possesses such as adenosine triphosphate synthesis, active transport of molecules, and rotation of bacterial flagella. Nevertheless, the potential of bacterial PMF as an antibacterial target remains largely unexplored. The PMF generally comprises electric potential (ΔΨ) and transmembrane proton gradient (ΔpH). In this review, we present an overview of bacterial PMF, including its functions and characterizations, highlighting the representative antimicrobial agents that specifically target either ΔΨ or ΔpH. At the same time, we also discuss the adjuvant potential of bacterial PMF-targeting compounds. Lastly, we highlight the value of PMF disruptors in preventing the transmission of antibiotic resistance genes. These findings suggest that bacterial PMF represents an unprecedented target, providing a comprehensive approach to controlling antimicrobial resistance.202336896761
908650.9806Emergence 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
818560.9805RNA-cleaving DNAzymes as a diagnostic and therapeutic agent against antimicrobial resistant bacteria. The development of nucleic-acid-based antimicrobials such as RNA-cleaving DNAzyme (RCD), a short catalytically active nucleic acid, is a promising alternative to the current antibiotics. The current rapid spread of antimicrobial resistance (AMR) in bacteria renders some antibiotics useless against bacterial infection, thus creating the need for alternative antimicrobials such as DNAzymes. This review summarizes recent advances in the use of RCD as a diagnostic and therapeutic agent against AMR. Firstly, the recent diagnostic application of RCD for the detection of bacterial cells and the associated resistant gene(s) is discussed. The next section summarises the therapeutic application of RCD in AMR bacterial infections which includes direct targeting of the resistant genes and indirect targeting of AMR-associated genes. Finally, this review extends the discussion to challenges of utilizing RCD in real-life applications, and the potential of combining both diagnostic and therapeutic applications of RCD into a single agent as a theranostic agent.202234505182
848570.9805Nonsteroidal anti-inflammatory drug diclofenac accelerates the emergence of antibiotic resistance via mutagenesis. Overuse of antimicrobial agents are generally considered to be a key factor in the occurrence of antibiotic resistance bacteria (ARB). Nevertheless, it is unclear whether ARB can be induced by non-antibiotic chemicals such as nonsteroidal anti-inflammatory drug (NSAID). Thus, the objective of this study is to investigate whether NSAID diclofenac (DCF) promote the emergence of antibiotic resistance in Escherichia coli K12 MG1655. Our results suggested that DCF induced the occurrence of ARB which showed hereditary stability of resistance. Meanwhile, gene variation was identified on chromosome of the ARB, and DCF can cause bacterial oxidative stress and SOS response. Subsequently, transcriptional levels of antioxidant (soxS, sodA, sodC, gor, katG, ahpF) and SOS (recA, lexA, uvrA, uvrB, ruvA, ruvB, dinB, umuC, polB) system-related genes were enhanced. However, the expression of related genes cannot be increased in high-dosage treatment compared with low-dosage samples because of cytotoxicity and cellular damage. Simultaneously, high-dosage DCF decreased the mutation frequency but enhanced the resistance of mutants. Our findings expand our knowledge of the promoting effect on the emergence of ARB caused by DCF. More attention and regulations should be given to these potential ecological and health risks for widespread DCF.202336958653
937280.9805The 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
600890.9805Photopolymerized keratin-PGLa hydrogels for antibiotic resistance reversal and enhancement of infectious wound healing. Infectious wounds have become serious challenges for both treatment and management in clinical practice, so development of new antibiotics has been considered an increasingly difficult task. Here, we report the design and synthesis of keratin 31 (K31)-peptide glycine-leucine-amide (PGLa) photopolymerized hydrogels to rescue the antibiotic activity of antibiotics for infectious wound healing promotion. K31-PGLa displayed an outstanding synergistic effect with commercial antibiotics against drug-resistant bacteria by down-regulating the synthesis genes of efflux pump. Furthermore, the photopolymerized K31-PGLa/PEGDA hydrogels effectively suppressed drug-resistant bacteria growth and enhanced skin wound closure in murine. This study provided a promising alternative strategy for infectious wound treatment.202337810750
9192100.9804Antimicrobial 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
9528110.9804Polycarbonates with Potent and Selective Antimicrobial Activity toward Gram-Positive Bacteria. The resistance developed by life-threatening bacteria toward conventional antibiotics has become a major concern in public health. To combat antibiotic resistance, there has been a significant interest in the development of antimicrobial cationic polymers due to the ease of synthesis and low manufacturing cost compared to host-defense peptides (HDPs). Herein, we report the design and synthesis of amphiphilic polycarbonates containing primary amino groups. These polymers exhibit potent antimicrobial activity and excellent selectivity to Gram-positive bacteria, including multidrug resistant pathogens. Fluorescence and TEM studies suggest that these polymers are likely to kill bacteria by disrupting bacterial membranes. These polymers also show low tendency to elicit resistance in bacteria. Their further development may lead to new antimicrobial agents combating drug-resistance.201728064500
9527120.9803Novel Opportunity to Reverse Antibiotic Resistance: To Explore Traditional Chinese Medicine With Potential Activity Against Antibiotics-Resistance Bacteria. Antibiotic resistance is becoming significantly prominent and urgent in clinical practice with the increasing and wide application of antibacterial drugs. However, developing and synthesizing new antimicrobial drugs is costly and time-consuming. Recently, researchers shifted their sights to traditional Chinese medicine (TCM). Here, we summarized the inhibitory mechanism of TCM herbs and their active ingredients on bacteria, discussed the regulatory mechanism of TCM on antibiotic-resistant bacteria, and revealed preclinical results of TCM herbs and their active components against antibiotic-resistant bacteria in mouse models. Those data suggest that TCM herbs and their effective constituents exhibit potential blockage ability on antibiotic-resistant bacteria, providing novel therapeutic ideas for reversing antibiotic resistance.202033414777
7492130.9803Elucidating the role of two types of essential oils in regulating antibiotic resistance in soil. Although several approaches for reducing antibiotic resistance genes (ARGs) in soil have been proposed, the application of environmentally friendly approaches is now attracting much more attention. In the present study, two types of essential oils (EOs), namely lavender essential oil (LEO) and oregano essential oil (OEO), were selected to investigate their roles in regulating ARGs in soil. In a 28-day microcosm experiment, it was found that the different types and doses of EOs significantly changed the composition of microbial communities. The LEO treatments enriched more taxa belonging to Actinobacteria than the control, whereas the low dose of OEO reduced Actinobacteria enrichment. Besides, the control and the treatments with a high dose of LEO and OEO all significantly enriched the functional pathways related to Human Diseases, which were positively associated with ARGs. However, the low dose of these EOs helped to reduce the pathways. Because of inhibition of the functional pathways and ARG hosts, the low dose of OEO reduce the ARGs related to antibiotic efflux by 71.8% and the resistance genes to multidrug by 56.4%, but these roles did not occur in LEO treatments. These outcomes provide practical and theoretical support for the application of EOs in remediating ARG-contaminated soils.202337094440
8135140.9803Harnessing Genome Editing Techniques to Engineer Disease Resistance in Plants. Modern genome editing (GE) techniques, which include clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) system, transcription activator-like effector nucleases (TALENs), zinc-finger nucleases (ZFNs) and LAGLIDADG homing endonucleases (meganucleases), have so far been used for engineering disease resistance in crops. The use of GE technologies has grown very rapidly in recent years with numerous examples of targeted mutagenesis in crop plants, including gene knockouts, knockdowns, modifications, and the repression and activation of target genes. CRISPR/Cas9 supersedes all other GE techniques including TALENs and ZFNs for editing genes owing to its unprecedented efficiency, relative simplicity and low risk of off-target effects. Broad-spectrum disease resistance has been engineered in crops by GE of either specific host-susceptibility genes (S gene approach), or cleaving DNA of phytopathogens (bacteria, virus or fungi) to inhibit their proliferation. This review focuses on different GE techniques that can potentially be used to boost molecular immunity and resistance against different phytopathogens in crops, ultimately leading to the development of promising disease-resistant crop varieties.201931134108
8437150.9802Tocopherol polyethylene glycol succinate-modified hollow silver nanoparticles for combating bacteria-resistance. Multiple drug resistance and the increase in the appearance of superbugs together with the exceedingly scant development of new potent antibiotic drugs pose an urgent global medical threat and imminent public security crisis. In the present study, we fabricated well-dispersed tocopherol polyethylene glycol succinate (TPGS)-capped silver nanoparticles (AgNPs) of about 10 nm in size. The hollow structure of the TPGS-capped AgNPs (TPGS/AgNPs) was confirmed and applied to load antibiotics. The TPGS/AgNPs proved to be able to cross the bacterial cell wall and penetrate into bacteria, thereby delivering more of the antibiotic to the interior of bacteria and thus enhancing the in vitro antibacterial effect of the antibiotic, even overcoming the drug-resistance in drug-resistant E. coli and Acinetobacter baumannii. It was found that the TPGS modification in the TPGS/AgNPs could decrease the activity of the efflux pumps AdeABC and AdeIJK in drug-resistant Acinetobacter baumannii via inhibiting the efflux pump genes adeB and adeJ, thus increasing the accumulation of the delivered antibiotic and overcoming the drug-resistance. Tigecycline delivered by TPGS/AgNPs could effectively antagonize drug-resistance in an acute peritonitis model mice, thereby increasing the survival rate and alleviating the inflammatory response. TPGS/AgNPs were developed as a novel and effective antibiotic delivery system and TPGS was demonstrated to have great potential as a pharmaceutical excipient for use in drug-resistant infection therapy.201930968093
8155160.9802Gut bacteria enable prostate cancer growth. Testosterone-synthetizing gut bacteria drive resistance to therapy.202134618567
7490170.9802Effect of Phorate on the Development of Hyperglycaemia in Mouse and Resistance Genes in Intestinal Microbiota. Phorate is a systemic, broad-spectrum organophosphorus insecticide. Although it is commonly used worldwide, phorate, like other pesticides, not only causes environmental pollution but also poses serious threats to human and animal health. Herein, we measured the blood glucose concentrations of high-fat-diet-fed mice exposed to various concentrations of phorate (0, 0.005, 0.05, or 0.5 mg/kg); we also assessed the blood glucose concentrations of high-fat-diet-fed mice exposed to phorate; we also assessed the distribution characteristics of the resistance genes in the intestinal microbiota of these mice. We found that 0.005 and 0.5 mg/kg of phorate induced obvious hyperglycaemia in the high-fat-diet-fed mice. Exposure to phorate markedly reduced the abundance of Akkermansia muciniphila in the mouse intestine. The resistance genes vanRG, tetW/N/W, acrD, and evgS were significantly upregulated in the test group compared with the control group. Efflux pumping was the primary mechanism of drug resistance in the Firmicutes, Proteobacteria, Bacteroidetes, Verrucomicrobia, Synergistetes, Spirochaetes, and Actinobacteria found in the mouse intestine. Our findings indicate that changes in the abundance of the intestinal microbiota are closely related to the presence of antibiotic-resistant bacteria in the intestinal tract and the metabolic health of the host.202236358236
8355180.9801Ecology-relevant bacteria drive the evolution of host antimicrobial peptides in Drosophila. Antimicrobial peptides are host-encoded immune effectors that combat pathogens and shape the microbiome in plants and animals. However, little is known about how the host antimicrobial peptide repertoire is adapted to its microbiome. Here, we characterized the function and evolution of the Diptericin antimicrobial peptide family of Diptera. Using mutations affecting the two Diptericins (Dpt) of Drosophila melanogaster, we reveal the specific role of DptA for the pathogen Providencia rettgeri and DptB for the gut mutualist Acetobacter. The presence of DptA- or DptB-like genes across Diptera correlates with the presence of Providencia and Acetobacter in their environment. Moreover, DptA- and DptB-like sequences predict host resistance against infection by these bacteria across the genus Drosophila. Our study explains the evolutionary logic behind the bursts of rapid evolution of an antimicrobial peptide family and reveals how the host immune repertoire adapts to changing microbial environments.202337471548
9162190.9801Joint effects of antibiotics and quorum sensing inhibitors on resistance development in bacteria. Quorum sensing inhibitors (QSIs) are promising alternatives to antibiotics. While QSIs have great application potential in a variety of fields, their joint effects with antibiotics on bacteria, especially on antibiotic resistance mutations, remain largely unexplored. Herein, we report the joint effects of four commonly used antibiotics and two QSIs on bacterial growth and resistance mutations in E. coli. It was found that QSIs presented antagonistic or additive effects with antibiotics on bacterial growth, and more importantly, QSIs exhibited an attenuating effect on antibiotic-induced resistance mutations. Further analysis demonstrated that antibiotics might enhance resistance mutations by promoting the expressions of rpoS, lexA and recA, while QSIs attenuated the mutations by promoting the expressions of mutS and uvrD. The present research provides a comprehensive understanding of the joint effects of antibiotics and QSIs on bacteria, which may benefit the risk assessment of their combined exposure.202134060581