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81300.8516Fighting against evolution of antibiotic resistance by utilizing evolvable antimicrobial drugs. Antibiotic resistance is a worldwide public health problem (Bush et al. in Nat Rev Microbiol 9:894-896, 2011). The lack of effective therapies against resistant bacteria globally leads to prolonged treatments, increased mortality, and inflating health care costs (Oz et al. in Mol Biol Evol 31:2387-2401, 2014; Martinez in Science 321:365-367, 2008; Lipsitch et al. in Proc Natl Acad Sci USA 97:1938-1943, 2000; Taubes in Science 321:356-361, 2008; Laxminarayan et al. in Lancet, 2016; Laxminarayan et al. in Lancet Infect Dis 13:1057-1098, 2013). Current efforts towards a solution of this problem can be boiled down to two main strategies: (1) developing of new antimicrobial agents and (2) searching for smart strategies that can restore or preserve the efficacy of existing antimicrobial agents. In this short review article, we discuss the need for evolvable antimicrobial agents, focusing on a new antimicrobial technology that utilizes peptide-conjugated phosphorodiamidate morpholino oligomers to inhibit the growth of pathogenic bacteria by targeting bacterial genes.201728497241
999810.8077mSphere of Influence: Uncovering New Ways To Control Multidrug Resistance by Dissecting Essential Cell Processes. Ana L. Flores-Mireles works in the fields of microbial pathogenesis and development of new therapeutics. In this mSphere of Influence article, she reflects on how the papers "Bacterial cell wall biogenesis is mediated by SEDS and PBP polymerase families functioning semi-autonomously" by H. Cho et al. (Nat Microbiol 1:16172, 2016, https://doi.org/10.1038/nmicrobiol.2016.172) and "A comprehensive, CRISPR-based functional analysis of essential genes in bacteria" by J. M. Peters et al. (Cell 165:1493-1506, 2016, https://doi.org/10.1016/j.cell.2016.05.003) made an impact on her approach to dissecting essential processes to understand microbial pathogenesis in catheter-associated urinary tract infections and generate an effective treatment with reduced likelihood of developing resistance.201931554727
905820.8032Antisense Agents against Antibiotic-resistant Bacteria. The dramatically increasing levels of antibiotic resistance are being seen worldwide and are a significant threat to public health. Antibiotic and drug resistance is seen in various bacterial species. Antibiotic resistance is associated with increased morbidity and mortality and increased treatment costs. Antisense-related technologies include oligonucleotides that interfere with gene transcription and expression; these oligonucleotides can help treat antibiotic-resistant bacteria. The important oligonucleotides include Peptide Nucleic Acids (PNAs), Phosphorodiamidate Morpholino Oligomers (PPMOs), and Locked Nucleic Acids (LNAs). Typically, the size of these structures (oligonucleotides) is 10 to 20 bases. PNAs, PPMOs, and LNAs are highlighted in this review as targets for genes that cause the gene to be destroyed and impede bacterial growth. These results open a new perspective for therapeutic intervention. Future studies need to examine different aspects of antisense agents, such as the safety, toxicity, and pharmacokinetic properties of antisense agents in clinical treatment.202235034590
81430.8030Drown Them in Their Own Garbage: a New Strategy To Reverse Polymyxin Resistance? Purcell and colleagues offer new insights into a major mechanism of polymyxin resistance in Gram-negative bacteria (A. B. Purcell, B. J. Voss, and M. S. Trent, J Bacteriol 204:e00498-21, 2022, https://doi.org/10.1128/JB.00498-21). Inactivating a single lipid recycling enzyme causes accumulation of waste lipid by-products that inhibit a key factor responsible for polymyxin resistance.202234843378
600840.8013Photopolymerized 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
815850.8006Nanobioconjugates: Weapons against Antibacterial Resistance. The increase in drug resistance in pathogenic bacteria is emerging as a global threat as we swiftly edge toward the postantibiotic era. Nanobioconjugates have gained tremendous attention to treat multidrug-resistant (MDR) bacteria and biofilms due to their tunable physicochemical properties, drug targeting ability, enhanced uptake, and alternate mechanisms of drug action. In this review, we highlight the recent advances made in the use of nanobioconjugates to combat antibacterial resistance and provide crucial insights for designing nanomaterials that can serve as antibacterial agents for nanotherapeutics, nanocargos for targeted antibiotic delivery, or both. Also discussed are different strategies for treating robust biofilms formed by bacteria.202035019602
783160.8000Integration of nanowire-confined electroporation of antibiotic-resistant bacteria and electroactivation of peracetic acid for eliminating intracellular resistance genes. Antimicrobial resistance is one of the most substantial challenges for global public health. To address the inefficient elimination of intracellular resistance genes (i-ARGs) in antibiotic-resistant bacteria (ARB) by peracetic acid (PAA) oxidation, we developed an integration strategy (NW-EP/EA) of nanowire-confined electroporation (NW-EP) of ARB cells and nanowire-confined electroactivation (NW-EA) of PAA with a sequential oxidation-reduction process. The locally enhanced electric field and electrocatalytic activity over NW tips prompted the formation of electroporation pores on ARB cells and the generation of reactive ⋅OH and RO⋅ radicals by PAA electroactivation. The NW-EP/EA with Pd-coated TiO(2)NW cathode with atomic H* evolution exhibited 0.6 -2.8-log higher i-ARG removal than the pristine TiO(2)NW cathode, especially achieving ∼5.0-log i-ARG removal (99.999 %) at 4.0 V and 2.0 mM PAA with ∼4.1-log synergistic effect and ∼10 times lower energy consumption as compared with the individual NW-EP (∼0.32-log and 52.1 %) and PAA (∼0.56-log and 74.4 %). For the sequential oxidation-reduction process, the electrooxidative activation of PAA on TiO(2)NW anode produced H(+) ions, ⋅OH and RO⋅ radicals for enlarging electroporation pores, and the generated H(+) ions promoted the evolution of atomic H* and electroreduction of PAA on subsequent Pd-TiO(2)NW cathode for further facilitating ARB cell damages, i-ARG leakage and degradation. The effective i-ARGs removal and HGT inhibition in tap water suggested the great application potentials of NW-EP/EA in the control of ARGs dissemination risks in drinking water.202540907311
816170.7997Integrative strategies against multidrug-resistant bacteria: Synthesizing novel antimicrobial frontiers for global health. Concerningly, multidrug-resistant bacteria have emerged as a prime worldwide trouble, obstructing the treatment of infectious diseases and causing doubts about the therapeutic accidentalness of presently existing drugs. Novel antimicrobial interventions deserve development as conventional antibiotics are incapable of keeping pace with bacteria evolution. Various promising approaches to combat MDR infections are discussed in this review. Antimicrobial peptides are examined for their broad-spectrum efficacy and reduced ability to develop resistance, while phage therapy may be used under extreme situations when antibiotics fail. In addition, the possibility of CRISPR-Cas systems for specifically targeting and eradicating resistance genes from bacterial populations will be explored. Nanotechnology has opened up the route to improve the delivery system of the drug itself, increasing the efficacy and specificity of antimicrobial action while protecting its host. Discovering potential antimicrobial agents is an exciting prospect through developments in synthetic biology and the rediscovery of natural product-based medicines. Moreover, host-directed therapies are now becoming popular as an adjunct to the main strategies of therapeutics without specifically targeting pathogens. Although these developments appear impressive, questions about production scaling, regulatory approvals, safety, and efficacy for clinical employment still loom large. Thus, tackling the MDR burden requires a multi-pronged plan, integrating newer treatment modalities with existing antibiotic regimens, enforcing robust stewardship initiatives, and effecting policy changes at the global level. The international health community can gird itself against the growing menace of antibiotic resistance if collaboration between interdisciplinary bodies and sustained research endeavours is encouraged. In this study, we evaluate the synergistic potential of combining various medicines in addition to summarizing recent advancements. To rethink antimicrobial stewardship in the future, we provide a multi-tiered paradigm that combines pathogen-focused and host-directed strategies.202540914328
4080.7988Combinative effects of a bacterial type-III effector and a biocontrol bacterium on rice growth and disease resistance. Expression of HpaG(Xoo), a bacterial type-III effector, in transgenic plants induces disease resistance. Resistance also can be elicited by biocontrol bacteria. In both cases, plant growth is often promoted. Here we address whether biocontrol bacteria and HpaG(Xoo) can act together to provide better results in crop improvement. We studied effects of Pseudomonas cepacia on the rice variety R109 and the hpaG(Xoo)-expressing rice line HER1. Compared to R109, HER1 showed increased growth, grain yield, and defense responses toward diseases and salinity stress. Colonization of roots by P. cepacia caused 20% and 13% increase, in contrast to controls, in root growth of R109 and HER1. Growth of leaves and stems also increased in R109 but that of HER1 was inhibited. When P. cepacia colonization was subsequent to plant inoculation with Rhizoctonia solani, a pathogen that causes sheath blight, the disease was less severe than controls in both R109 and HER1; HER1, nevertheless, was more resistant, suggesting that P. cepacia and HpaG(Xoo) cooperate in inducing disease resistance. Several genes that critically regulate growth and defense behaved differentially in HER1 and R109 while responding to P. cepacia. In R109 leaves, the OsARF1 gene, which regulates plant growth, was expressed in consistence with growth promotion by P. cepacia. Inversely, OsARF1 expression was coincident with inhibition in growth of HER1 leaves. In both plants, the expression of OsEXP1, which encodes an expansin protein involved in plant growth,was concomitant with growth promotion in leaves instead of roots,in response to P. cepacia . We also studied OsMAPK, a gene that encodes a mitogen-activated protein kinase and controls defense responses toward salinity and infection by pathogens in rice. In response to P. cepacia, an early expression of OsMAPK was coincident with R109 resistance to the disease, while HER1 expressed the gene similarly whether P. cepacia was present or not. Evidently, P. cepacia and G(Xoo)-gene mediated resistance may act differently in rice growth and resistance. Whereas combinative effects of P. cepacia and HpaG(Xoo) in disease resistance have a great potential in agricultural use, it is interesting to study mechanisms that underlie interactions involving biocontrol bacteria, type-III effectors and pathogens.200617301500
905090.7980Cationic Polysaccharide Conjugates as Antibiotic Adjuvants Resensitize Multidrug-Resistant Bacteria and Prevent Resistance. In recent years, traditional antibiotic efficacy has rapidly diminished due to the advent of multidrug-resistant (MDR) bacteria, which poses severe threat to human life and globalized healthcare. Currently, the development cycle of new antibiotics cannot match the ongoing MDR infection crisis. Therefore, novel strategies are required to resensitize MDR bacteria to existing antibiotics. In this study, novel cationic polysaccharide conjugates Dextran-graft-poly(5-(1,2-dithiolan-3-yl)-N-(2-guanidinoethyl)pentanamide) (Dex-g-PSS(n) ) is synthesized using disulfide exchange polymerization. Critically, bacterial membranes and efflux pumps are disrupted by a sub-inhibitory concentration of Dex-g-PSS(30) , which enhances rifampicin (RIF) accumulation inside bacteria and restores its efficacy. Combined Dex-g-PSS(30) and RIF prevents bacterial resistance in bacteria cultured over 30 generations. Furthermore, Dex-g-PSS(30) restores RIF effectiveness, reduces inflammatory reactions in a pneumonia-induced mouse model, and exhibits excellent in vivo biological absorption and degradation capabilities. As an antibiotic adjuvant, Dex-g-PSS(30) provides a novel resensitizing strategy for RIF against MDR bacteria and bacterial resistance. This Dex-g-PSS(30) research provides a solid platform for future MDR applications.202235962720
9746100.7980Fluoroamphiphilic polymers exterminate multidrug-resistant Gram-negative ESKAPE pathogens while attenuating drug resistance. ESKAPE pathogens are a panel of most recalcitrant bacteria that could "escape" the treatment of antibiotics and exhibit high incidence of drug resistance. The emergence of multidrug-resistant (MDR) ESKAPE pathogens (particularly Gram-negative bacteria) accounts for high risk of mortality and increased resource utilization in health care. Worse still, there has been no new class of antibiotics approved for exterminating the Gram-negative bacteria for more than 50 years. Therefore, it is urgent to develop novel antibacterial agents with low resistance and potent killing efficacy against Gram-negative ESKAPE pathogens. Herein, we present a class of fluoropolymers by mimicking the amphiphilicity of cationic antimicrobial peptides. Our optimal fluoroamphiphilic polymer (PD(45)HF(5)) displayed selective antimicrobial ability for all MDR Gram-negative ESAKPE pathogens, low resistance, high in vitro cell selectivity, and in vivo curative efficacy. These findings implied great potential of fluoroamphiphilic cationic polymers as promising antibacterial agents against MDR Gram-negative ESKAPE bacteria and alleviating antibiotic resistance.202439196947
8185110.7977RNA-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
8176120.7972Overcoming Multidrug Resistance in Bacteria Through Antibiotics Delivery in Surface-Engineered Nano-Cargos: Recent Developments for Future Nano-Antibiotics. In the recent few decades, the increase in multidrug-resistant (MDR) bacteria has reached an alarming rate and caused serious health problems. The incidence of infections due to MDR bacteria has been accompanied by morbidity and mortality; therefore, tackling bacterial resistance has become an urgent and unmet challenge to be properly addressed. The field of nanomedicine has the potential to design and develop efficient antimicrobials for MDR bacteria using its innovative and alternative approaches. The uniquely constructed nano-sized antimicrobials have a predominance over traditional antibiotics because their small size helps them in better interaction with bacterial cells. Moreover, surface engineering of nanocarriers offers significant advantages of targeting and modulating various resistance mechanisms, thus owe superior qualities for overcoming bacterial resistance. This review covers different mechanisms of antibiotic resistance, application of nanocarrier systems in drug delivery, functionalization of nanocarriers, application of functionalized nanocarriers for overcoming bacterial resistance, possible limitations of nanocarrier-based approach for antibacterial delivery, and future of surface-functionalized antimicrobial delivery systems.202134307323
8160130.7970Quorum Sensing in Gram-Negative Bacteria: Strategies to Overcome Antibiotic Resistance in Ocular Infections. Truly miraculous medications and antibiotics have helped save untold millions of lives. Antibiotic resistance, however, is a significant issue related to health that jeopardizes the effectiveness of antibiotics and could harm everyone's health. Bacteria, not humans or animals, become antibiotic-resistant. Bacteria use quorum-sensing communication routes to manage an assortment of physiological exercises. Quorum sensing is significant for appropriate biofilm development. Antibiotic resistance occurs when bacteria establish a biofilm on a surface, shielding them from the effects of infection-fighting drugs. Acylated homoserine lactones are used as autoinducers by gram-negative microscopic organisms to impart. However, antibiotic resistance among ocular pathogens is increasing worldwide. Bacteria are a significant contributor to ocular infections around the world. Gram-negative microscopic organisms are dangerous to ophthalmic tissues. This review highlights the use of elective drug targets and treatments, for example, combinational treatment, to vanquish antibiotic-resistant bacteria. Also, it briefly portrays anti-biotic resistance brought about by gram-negative bacteria and approaches to overcome resistance with the help of quorum sensing inhibitors and nanotechnology as a promising medication conveyance approach to give insurance of anti-microbials and improve pathways for the administration of inhibitors of quorum sensing with a blend of anti-microbials to explicit target destinations and penetration through biofilms for treatment of ocular infections. It centres on the methodologies to sidestep the confinements of ocular anti-biotic delivery with new visual innovation.202437497706
8162140.7969Nanotechnology for Targeted Detection and Removal of Bacteria: Opportunities and Challenges. The emergence of nanotechnology has created unprecedented hopes for addressing several unmet industrial and clinical issues, including the growing threat so-termed "antibiotic resistance" in medicine. Over the last decade, nanotechnologies have demonstrated promising applications in the identification, discrimination, and removal of a wide range of pathogens. Here, recent insights into the field of bacterial nanotechnology are examined that can substantially improve the fundamental understanding of nanoparticle and bacteria interactions. A wide range of developed nanotechnology-based approaches for bacterial detection and removal together with biofilm eradication are summarized. The challenging effects of nanotechnologies on beneficial bacteria in the human body and environment and the mechanisms of bacterial resistance to nanotherapeutics are also reviewed.202134558234
8135150.7968Harnessing 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
9524160.7967The Role of Nitroreductases in Resistance to Nitroimidazoles. Antimicrobial resistance is a major challenge facing modern medicine, with an estimated 700,000 people dying annually and a global cost in excess of $100 trillion. This has led to an increased need to develop new, effective treatments. This review focuses on nitroimidazoles, which have seen a resurgence in interest due to their broad spectrum of activity against anaerobic Gram-negative and Gram-positive bacteria. The role of nitroreductases is to activate the antimicrobial by reducing the nitro group. A decrease in the activity of nitroreductases is associated with resistance. This review will discuss the resistance mechanisms of different disease organisms, including Mycobacterium tuberculosis, Helicobacter pylori and Staphylococcus aureus, and how these impact the effectiveness of specific nitroimidazoles. Perspectives in the field of nitroimidazole drug development are also summarised.202134062712
4445170.7966Genomic Analysis and Resistance Mechanisms in Shigella flexneri 2a Strain 301. Shigella flexneri is one of the most prominent pathogenic bacteria in developing countries. In the battle against shigellosis and other bacterial diseases, antibiotic resistance has become an increasing global public health threat. Although the serious phenomenon of multidrug resistance (MDR) has been identified as one of the top three burdens on human health, resistance mechanisms are still poorly understood at the molecular level. In this study, we analyzed genomic data and the evolution of resistance in Shigella flexneri under sequential selection stress from three separate antibiotics: ciprofloxacin (CIP), ceftriaxone (CRO), and tetracycline. Through whole-genome sequencing, 82 chromosomal antibiotic resistance genes were identified. Re-sequencing of the evolved populations identified single nucleotide polymorphisms (SNPs) that contributed to MDR and SNPs that were specific to a single drug. A total of 40 SNPs in 8 genes and 3 intergenic regions, including mutations in metG (L582R) and 1538924, 1538924, and 1538924, appeared under each antibiotic. Several nonsynonymous mutations in gyrB (S464Y), ydgA (E378A), rob (R156H), and narX (K75E) were observed under selective pressure from CIP or CRO. Based on a bioinformatic analysis and previous reports, we discuss the contribution of these mutated genes to resistance. Therefore, more circumspect selection and use of antimicrobial drugs for treating shigellosis is necessary.201828853989
8746180.7966Enhanced Resistance to Fungal and Bacterial Diseases Due to Overexpression of BSR1, a Rice RLCK, in Sugarcane, Tomato, and Torenia. Sugarcane smut caused by Sporisorium scitamineum is one of the most devastating sugarcane diseases. Furthermore, Rhizoctonia solani causes severe diseases in various crops including rice, tomato, potato, sugar beet, tobacco, and torenia. However, effective disease-resistant genes against these pathogens have not been identified in target crops. Therefore, the transgenic approach can be used since conventional cross-breeding is not applicable. Herein, the overexpression of BROAD-SPECTRUM RESISTANCE 1 (BSR1), a rice receptor-like cytoplasmic kinase, was conducted in sugarcane, tomato and torenia. BSR1-overexpressing tomatoes exhibited resistance to the bacteria Pseudomonas syringae pv. tomato DC3000 and the fungus R. solani, whereas BSR1-overexpressing torenia showed resistance to R. solani in the growth room. Additionally, BSR1 overexpression conferred resistance to sugarcane smut in the greenhouse. These three BSR1-overexpressing crops exhibited normal growth and morphologies except in the case of exceedingly high levels of overexpression. These results indicate that BSR1 overexpression is a simple and effective tool for conferring broad-spectrum disease resistance to many crops.202336835053
8180190.7964Harnessing Nanoparticles to Overcome Antimicrobial Resistance: Promises and Challenges. The rise of antimicrobial resistance (AMR) has become a serious global health issue that kills millions of people each year globally. AMR developed in bacteria is difficult to treat and poses a challenge to clinicians. Bacteria develop resistance through a variety of processes, including biofilm growth, targeted area alterations, and therapeutic drug alteration, prolonging the period they remain within cells, where antibiotics are useless at therapeutic levels. This rise in resistance is linked to increased illness and death, highlighting the urgent need for effective solutions to combat this growing challenge. Nanoparticles (NPs) offer unique solutions for fighting AMR bacteria. Being smaller in size with a high surface area, enhancing interaction with bacteria makes the NPs strong antibacterial agents against various infections. In this review, we have discussed the epidemiology and mechanism of AMR development. Furthermore, the role of nanoparticles as antibacterial agents, and their role in drug delivery has been addressed. Additionally, the potential, challenges, toxicity, and future prospects of nanoparticles as antibacterial agents against AMR pathogens have been discussed. The research work discussed in this review links with Sustainable Development Goal 3 (SDG-3), which aims to ensure disease-free lives and promote well-being for all ages.202539219123