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973400.9876Combination of genetically diverse Pseudomonas phages enhances the cocktail efficiency against bacteria. Phage treatment has been used as an alternative to antibiotics since the early 1900s. However, bacteria may acquire phage resistance quickly, limiting the use of phage treatment. The combination of genetically diverse phages displaying distinct replication machinery in phage cocktails has therefore become a novel strategy to improve therapeutic outcomes. Here, we isolated and studied lytic phages (SPA01 and SPA05) that infect a wide range of clinical Pseudomonas aeruginosa isolates. These relatively small myophages have around 93 kbp genomes with no undesirable genes, have a 30-min latent period, and reproduce a relatively high number of progenies, ranging from 218 to 240 PFU per infected cell. Even though both phages lyse their hosts within 4 h, phage-resistant bacteria emerge during the treatment. Considering SPA01-resistant bacteria cross-resist phage SPA05 and vice versa, combining SPA01 and SPA05 for a cocktail would be ineffective. According to the decreased adsorption rate of the phages in the resistant isolates, one of the anti-phage mechanisms may occur through modification of phage receptors on the target cells. All resistant isolates, however, are susceptible to nucleus-forming jumbophages (PhiKZ and PhiPA3), which are genetically distinct from phages SPA01 and SPA05, suggesting that the jumbophages recognize a different receptor during phage entry. The combination of these phages with the jumbophage PhiKZ outperforms other tested combinations in terms of bactericidal activity and effectively suppresses the emergence of phage resistance. This finding reveals the effectiveness of the diverse phage-composed cocktail for reducing bacterial growth and prolonging the evolution of phage resistance.202337264114
518310.9869Development of phage resistance in multidrug-resistant Klebsiella pneumoniae is associated with reduced virulence: a case report of a personalised phage therapy. OBJECTIVES: Phage-resistant bacteria often emerge rapidly when performing phage therapy. However, the relationship between the emergence of phage-resistant bacteria and improvements in clinical symptoms is still poorly understood. METHODS: An inpatient developed a pulmonary infection caused by multidrug-resistant Klebsiella pneumoniae. He received a first course of treatment with a single nebulized phage (ΦKp_GWPB35) targeted at his bacterial isolate of Kp7450. After 14 days, he received a second course of treatment with a phage cocktail (ΦKp_GWPB35+ΦKp_GWPA139). Antibiotic treatment was continued throughout the course of phage therapy. Whole-genome analysis was used to identify mutations in phage-resistant strains. Mutated genes associated with resistance were further analysed by generating knockouts of Kp7450 and by measuring phage adsorption rates of bacteria treated with proteinase K and periodate. Bacterial virulence was evaluated in mouse and zebrafish infection models. RESULTS: Phage-resistant Klebsiella pneumoniae strains emerged after the second phage treatment. Comparative genomic analyses revealed that fabF was deleted in phage-resistant strains. The fabF knockout strain (Kp7450ΔfabF) resulted in an altered structure of lipopolysaccharide (LPS), which was identified as the host receptor for the therapeutic phages. Virulence evaluations in mice and zebrafish models showed that LPS was the main determinant of virulence in Kp7450 and alteration of LPS structure in Kp7450ΔfabF, and the bacteriophage-resistant strains reduced their virulence at cost. DISCUSSION: This study may shed light on the mechanism by which some patients experience clinical improvement in their symptoms post phage therapy, despite the incomplete elimination of pathogenic bacteria.202337652124
905620.9858Antibacterial potential of hGlyrichin encoded by a human gene. Emerging multidrug-resistant (MDR) bacteria are an enormous threat to human life because of their resistance to currently available antibiotics. The genes encoding antibacterial peptides have been studied extensively and are excellent candidates for a new generation of antibiotic drugs to fight MDR bacteria. In contrast to traditional antibiotics, antibacterial peptides, which do not cause drug resistance, have an unparalleled advantage. However, because most antibacterial peptides originate in species other than humans, the hetero-immunological rejection of antibacterial peptides is a key disadvantage that limits their clinical application. In this study, we identify hGlyrichin as a potential human antibacterial polypeptide. The hGlyrichin polypeptide kills a variety of bacteria including the MDR bacteria methicillin-resistant Staphylococcus aureus, MDR Pseudomonas aeruginosa, and MDR tubercle bacillus. A 19 amino acid peptide (pCM19) at positions 42-60 of hGlyrichin is crucial for its antibacterial activity. The hGlyrichin polypeptide kills bacteria through the destruction of the bacterial membrane. In addition, all peptides that are homologous to hGlyrichin have antibacterial activity and can penetrate the bacterial membrane. Importantly, hGlyrichin does not cause hemolytic side effects in vitro or in vivo. Therefore, based on the virtues of hGlyrichin, i.e., the absence of hetero-immunological rejection and hemolytic side effects and the unambiguous efficacy of killing pathogenic MDR bacteria, we propose hGlyrichin as a potential human antibacterial polypeptide.201222083756
813130.9855Effects of levodopa on gut bacterial antibiotic resistance in Parkinson's disease rat. The second most prevalent neurodegenerative ailment, Parkinson's disease (PD), is characterized by both motor and non-motor symptoms. Levodopa is the backbone of treatment for PD at the moment. However, levodopa-induced side effects, such as dyskinesia, are commonly seen in PD patients. Recently, several antibiotics were found to present neuroprotective properties against neurodegenerative and neuro-inflammatory processes, which might be developed to effective therapies against PD. In this study, we aimed to identify if levodopa treatment could influence the gut bacterial antibiotic resistance in PD rat. Fecal samples were collected from healthy rats and 6-OHDA induced PD rats treated with different doses of levodopa, metagenomic sequencing data showed that levodopa resulted in gut bacteria composition change, the biomarkers of gut bacteria analyzed by LEfSe changed as well. More interestingly, compared with levodopa (5 mg/kg)-treated or no levodopa-treated PD rats, levodopa (10 mg/kg) caused a significant decrease in the abundance of tetW and vanTG genes in intestinal bacteria, which were related to tetracycline and vancomycin resistance, while the abundance of AAC6-lb-Suzhou gene increased apparently, which was related to aminoglycosides resistance, even though the total quantity of Antibiotic Resistance Gene (ARG) and Antibiotic Resistance Ontology (ARO) among all groups did not significantly differ. Consequently, our results imply that the combination of levodopa and antibiotics, such as tetracycline and vancomycin, in the treatment of PD may decrease the amount of corresponding antibiotic resistance genes in gut bacteria, which would give a theoretical basis for treating PD with levodopa combined with tetracycline and vancomycin in the future.202336824263
517440.9854Characterization of ES10 lytic bacteriophage isolated from hospital waste against multidrug-resistant uropathogenic E. coli. Escherichia coli is the major causative agent of urinary tract infections worldwide and the emergence of multi-drug resistant determinants among clinical isolates necessitates the development of novel therapeutic agents. Lytic bacteriophages efficiently kill specific bacteria and seems promising approach in controlling infections caused by multi-drug resistant pathogens. This study aimed the isolation and detailed characterization of lytic bacteriophage designated as ES10 capable of lysing multidrug-resistant uropathogenic E. coli. ES10 had icosahedral head and non-contractile tail and genome size was 48,315 base pairs long encoding 74 proteins. Antibiotics resistance, virulence and lysogenic cycle associated genes were not found in ES10 phage genome. Morphological and whole genome analysis of ES10 phage showed that ES10 is the member of Drexlerviridae. Latent time of ES10 was 30 min, burst size was 90, and optimal multiplicity of infection was 1. ES10 was stable in human blood and subsequently caused 99.34% reduction of host bacteria. Calcium chloride shortened the adsorption time and latency period of ES10 and significantly inhibited biofilm formation of host bacteria. ES10 caused 99.84% reduction of host bacteria from contaminated fomites. ES10 phage possesses potential to be utilized in standard phage therapy.202438525078
884650.9851Phage Resistance Accompanies Reduced Fitness of Uropathogenic Escherichia coli in the Urinary Environment. Urinary tract infection (UTI) is among the most common infections treated worldwide each year and is caused primarily by uropathogenic Escherichia coli (UPEC). Rising rates of antibiotic resistance among uropathogens have spurred a consideration of alternative treatment strategies, such as bacteriophage (phage) therapy; however, phage-bacterial interactions within the urinary environment are poorly defined. Here, we assess the activity of two phages, namely, HP3 and ES17, against clinical UPEC isolates using in vitro and in vivo models of UTI. In both bacteriologic medium and pooled human urine, we identified phage resistance arising within the first 6 to 8 h of coincubation. Whole-genome sequencing revealed that UPEC strains resistant to HP3 and ES17 harbored mutations in genes involved in lipopolysaccharide (LPS) biosynthesis. Phage-resistant strains displayed several in vitro phenotypes, including alterations to adherence to and invasion of human bladder epithelial HTB-9 cells and increased biofilm formation in some isolates. Interestingly, these phage-resistant UPEC isolates demonstrated reduced growth in pooled human urine, which could be partially rescued by nutrient supplementation and were more sensitive to several outer membrane-targeting antibiotics than parental strains. Additionally, phage-resistant UPEC isolates were attenuated in bladder colonization in a murine UTI model. In total, our findings suggest that while resistance to phages, such as HP3 and ES17, may arise readily in the urinary environment, phage resistance is accompanied by fitness costs which may render UPEC more susceptible to host immunity or antibiotics. IMPORTANCE UTI is one of the most common causes of outpatient antibiotic use, and rising antibiotic resistance threatens the ability to control UTI unless alternative treatments are developed. Bacteriophage (phage) therapy is gaining renewed interest; however, much like with antibiotics, bacteria can readily become resistant to phages. For successful UTI treatment, we must predict how bacteria will evade killing by phage and identify the downstream consequences of phage resistance during bacterial infection. In our current study, we found that while phage-resistant bacteria quickly emerged in vitro, these bacteria were less capable of growing in human urine and colonizing the murine bladder. These results suggest that phage therapy poses a viable UTI treatment if phage resistance confers fitness costs for the uropathogen. These results have implications for developing cocktails of phage with multiple different bacterial targets, of which each is evaded only at the cost of bacterial fitness.202235920561
843360.9850Thermoresponsive 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
973570.9850Arms race and fluctuating selection dynamics in Pseudomonas aeruginosa bacteria coevolving with phage OMKO1. Experimental evolution studies have examined coevolutionary dynamics between bacteria and lytic phages, where two models for antagonistic coevolution dominate: arms-race dynamics (ARD) and fluctuating-selection dynamics (FSD). Here, we tested the ability for Pseudomonas aeruginosa to coevolve with phage OMKO1 during 10 passages in the laboratory, whether ARD versus FSD coevolution occurred, and how coevolution affected a predicted phenotypic trade-off between phage resistance and antibiotic sensitivity. We used a unique "deep" sampling design, where 96 bacterial clones per passage were obtained from the three replicate coevolving communities. Next, we examined phenotypic changes in growth ability, susceptibility to phage infection and resistance to antibiotics. Results confirmed that the bacteria and phages coexisted throughout the study with one community undergoing ARD, whereas the other two showed evidence for FSD. Surprisingly, only the ARD bacteria demonstrated the anticipated trade-off. Whole genome sequencing revealed that treatment populations of bacteria accrued more de novo mutations, relative to a control bacterial population. Additionally, coevolved bacteria presented mutations in genes for biosynthesis of flagella, type-IV pilus and lipopolysaccharide, with three mutations fixing contemporaneously with the occurrence of the phenotypic trade-off in the ARD-coevolved bacteria. Our study demonstrates that both ARD and FSD coevolution outcomes are possible in a single interacting bacteria-phage system and that occurrence of predicted phage-driven evolutionary trade-offs may depend on the genetics underlying evolution of phage resistance in bacteria. These results are relevant for the ongoing development of lytic phages, such as OMKO1, in personalized treatment of human patients, as an alternative to antibiotics.202236168737
909180.9849Characterization of an Enterococcus faecalis Bacteriophage vB_EfaM_LG1 and Its Synergistic Effect With Antibiotic. Enterococcus faecalis is a Gram-positive opportunistic pathogen that could cause pneumonia and bacteremia in stroke patients. The development of antibiotic resistance in hospital-associated E. faecalis is a formidable public health threat. Bacteriophage therapy is a renewed solution to treat antibiotic-resistant bacterial infections. However, bacteria can acquire phage resistance quite quickly, which is a significant barrier to phage therapy. Here, we characterized a lytic E. faecalis bacteriophage Vb_EfaM_LG1 with lytic activity. Its genome did not contain antibiotic resistance or virulence genes. Vb_EfaM_LG1 effectively inhibits E. faecalis growth for a short period, and phage resistance developed within hours. However, the combination of antibiotics and phage has a tremendous synergistic effect against E. faecalis, prevents the development of phage resistance, and disrupts the biofilm efficiently. Our results show that the phage-antibiotic combination has better killing efficiency against E. faecalis.202134336721
909090.9848Defeating Antibiotic- and Phage-Resistant Enterococcus faecalis Using a Phage Cocktail in Vitro and in a Clot Model. The deteriorating effectiveness of antibiotics is propelling researchers worldwide towards alternative techniques such as phage therapy: curing infectious diseases using viruses of bacteria called bacteriophages. In a previous paper, we isolated phage EFDG1, highly effective against both planktonic and biofilm cultures of one of the most challenging pathogenic species, the vancomycin-resistant Enterococcus (VRE). Thus, it is a promising phage to be used in phage therapy. Further experimentation revealed the emergence of a mutant resistant to EFDG1 phage: EFDG1(r). This kind of spontaneous resistance to antibiotics would be disastrous occurrence, however for phage-therapy it is only a minor hindrance. We quickly and successfully isolated a new phage, EFLK1, which proved effective against both the resistant mutant EFDG1(r) and its parental VRE, Enterococcus faecalis V583. Furthermore, combining both phages in a cocktail produced an additive effect against E. faecalis V583 strains regardless of their antibiotic or phage-resistance profile. An analysis of the differences in genome sequence, genes, mutations, and tRNA content of both phages is presented. This work is a proof-of-concept of one of the most significant advantages of phage therapy, namely the ability to easily overcome emerging resistant bacteria.201829541067
5168100.9847Bacteriophage Resistance Affects Flavobacterium columnare Virulence Partly via Mutations in Genes Related to Gliding Motility and the Type IX Secretion System. Increasing problems with antibiotic resistance have directed interest toward phage therapy in the aquaculture industry. However, phage resistance evolving in target bacteria is considered a challenge. To investigate how phage resistance influences the fish pathogen Flavobacterium columnare, two wild-type bacterial isolates, FCO-F2 and FCO-F9, were exposed to phages (FCO-F2 to FCOV-F2, FCOV-F5, and FCOV-F25, and FCO-F9 to FCL-2, FCOV-F13, and FCOV-F45), and resulting phenotypic and genetic changes in bacteria were analyzed. Bacterial viability first decreased in the exposure cultures but started to increase after 1 to 2 days, along with a change in colony morphology from original rhizoid to rough, leading to 98% prevalence of the rough morphotype. Twenty-four isolates (including four isolates from no-phage treatments) were further characterized for phage resistance, antibiotic susceptibility, motility, adhesion, and biofilm formation, protease activity, whole-genome sequencing, and virulence in rainbow trout fry. The rough isolates arising in phage exposure were phage resistant with low virulence, whereas rhizoid isolates maintained phage susceptibility and high virulence. Gliding motility and protease activity were also related to the phage susceptibility. Observed mutations in phage-resistant isolates were mostly located in genes encoding the type IX secretion system, a component of the Bacteroidetes gliding motility machinery. However, not all phage-resistant isolates had mutations, indicating that phage resistance in F. columnare is a multifactorial process, including both genetic mutations and changes in gene expression. Phage resistance may not, however, be a challenge for development of phage therapy against F. columnare infections since phage resistance is associated with decreases in bacterial virulence. IMPORTANCE Phage resistance of infectious bacteria is a common phenomenon posing challenges for the development of phage therapy. Along with a growing world population and the need for increased food production, constantly intensifying animal farming has to face increasing problems of infectious diseases. Columnaris disease, caused by Flavobacterium columnare, is a worldwide threat for salmonid fry and juvenile farming. Without antibiotic treatments, infections can lead to 100% mortality in a fish stock. Phage therapy of columnaris disease would reduce the development of antibiotic-resistant bacteria and antibiotic loads by the aquaculture industry, but phage-resistant bacterial isolates may become a risk. However, phenotypic and genetic characterization of phage-resistant F. columnare isolates in this study revealed that they are less virulent than phage-susceptible isolates and thus not a challenge for phage therapy against columnaris disease. This is valuable information for the fish farming industry globally when considering phage-based prevention and curing methods for F. columnare infections.202134106011
8159110.9847Quaternary Ammonium Salts: Insights into Synthesis and New Directions in Antibacterial Applications. The overuse of antibiotics has led to the emergence of a large number of antibiotic-resistant genes in bacteria, and increasing evidence indicates that a fungicide with an antibacterial mechanism different from that of antibiotics is needed. Quaternary ammonium salts (QASs) are a biparental substance with good antibacterial properties that kills bacteria through simple electrostatic adsorption and insertion into cell membranes/altering of cell membrane permeability. Therefore, the probability of bacteria developing drug resistance is greatly reduced. In this review, we focus on the synthesis and application of single-chain QASs, double-chain QASs, heterocyclic QASs, and gemini QASs (GQASs). Some possible structure-function relationships of QASs are also summarized. As such, we hope this review will provide insight for researchers to explore more applications of QASs in the field of antimicrobials with the aim of developing systems for clinical applications.202336748912
9010120.9846Recovering the susceptibility of antibiotic-resistant bacteria using photooxidative damage. Multidrug-resistant bacteria are one of the most serious threats to infection control. Few new antibiotics have been developed; however, the lack of an effective new mechanism of their action has worsened the situation. Photodynamic inactivation (PDI) can break antimicrobial resistance, since it potentiates the effect of antibiotics, and induces oxidative stress in microorganisms through the interaction of light with a photosensitizer. This paper addresses the application of PDI for increasing bacterial susceptibility to antibiotics and helping in bacterial persistence and virulence. The effect of photodynamic action on resistant bacteria collected from patients and bacteria cells with induced resistance in the laboratory was investigated. Staphylococcus aureus resistance breakdown levels for each antibiotic (amoxicillin, erythromycin, and gentamicin) from the photodynamic effect (10 µM curcumin, 10 J/cm(2)) and its maintenance in descendant microorganisms were demonstrated within five cycles after PDI application. PDI showed an innovative feature for modifying the degree of bacterial sensitivity to antibiotics according to dosages, thus reducing resistance and persistence of microorganisms from standard and clinical strains. We hypothesize a reduction in the degree of antimicrobial resistance through photooxidative action combats antibiotic failures.202337729197
9471130.9846Systematic analysis of putative phage-phage interactions on minimum-sized phage cocktails. The application of bacteriophages as antibacterial agents has many benefits in the "post-antibiotic age". To increase the number of successfully targeted bacterial strains, phage cocktails, instead of a single phage, are commonly formulated. Nevertheless, there is currently no consensus pipeline for phage cocktail development. Thus, although large cocktails increase the spectrum of activity, they could produce side effects such as the mobilization of virulence or antibiotic resistance genes. On the other hand, coinfection (simultaneous infection of one host cell by several phages) might reduce the potential for bacteria to evolve phage resistance, but some antagonistic interactions amongst phages might be detrimental for the outcome of phage cocktail application. With this in mind, we introduce here a new method, which considers the host range and each individual phage-host interaction, to design the phage mixtures that best suppress the target bacteria while minimizing the number of phages to restrict manufacturing costs. Additionally, putative phage-phage interactions in cocktails and phage-bacteria networks are compared as the understanding of the complex interactions amongst bacteriophages could be critical in the development of realistic phage therapy models in the future.202235165352
9026140.9845Citral and its derivatives inhibit quorum sensing and biofilm formation in Chromobacterium violaceum. With an upsurge in multidrug resistant bacteria backed by biofilm defence armours, there is a desperate need of new antibiotics with a non-traditional mechanism of action. Targeting bacteria by misguiding them or halting their communication is a new approach that could offer a new way to combat the multidrug resistance problem. Quorum sensing is considered to be the achilles heel of bacteria that has a lot to offer. Since, both quorum sensing and biofilm formation have been related to drug resistance and pathogenicity, in this study we synthesised new derivatives of citral with antiquorum sensing and biofilm disrupting properties. We previously reported antimicrobial and antiquorum sensing activity of citral and herein we report the synthesis and evaluation of citral and its derivatives (CD1-CD3) for antibacterial, antibiofilm and antiquorum sensing potential against Chromobacterium violaceum using standard methods. Preliminary results revealed that CD1 is the most active of all the derivatives. Qualitative and quantitative evaluation of antiquorum sensing activity at sub-inhibitory concentrations of these compounds also revealed high activity for CD1 followed by CD2, CD3 and citral. These compounds also inhibit biofilm formation at subinhibitory concentrations without causing any bacterial growth inhibition. These results were replicated by RT-qPCR with down regulation of the quorum sensing genes when C. violaceum was treated with these test compounds. Overall, the results are quite encouraging, revealing that biofilm and quorum sensing are interrelated processes and also indicating the potential of these derivatives to impede bacterial communication and biofilm formation.202133392626
8478150.9845Developing japonica rice introgression lines with multiple resistance genes for brown planthopper, bacterial blight, rice blast, and rice stripe virus using molecular breeding. Yield losses as a result of biotic stresses by fungi, bacteria, viruses, and insects are a key challenge in most rice cultivation areas. The development of resistant cultivars is considered an efficient and sustainable approach to mitigate rice yield reduction. In the present study, we describe the development of japonica rice introgression lines with multiple resistance genes (MR lines), resistant to four different types of biotic stresses, and compare the agronomic performance, yield, and grain quality parameters of these lines with those of the recurrent parent. A total of nine MR lines were developed by marker-assisted backcrossing, which combined five single-R genes in a japonica background with a minimum of linkage drag. All the MR lines harbored the R genes Bph18 and qSTV11(SG) and two Pi genes (Pib + Pik) in common, offering resistance to brown planthopper (BPH), rice stripe virus (RSV), and rice blast disease, respectively. In the case of bacterial blight (BB), Xa40 was detected in only five out of the nine and Xa3 was validated in the others. In particular, the five MR lines pyramiding the R genes (Bph18 + qSTV11SG + Pib + Pik) in combination with Xa40 showed stable resistance to all bioassays for BPH, BB, blast, and RSV. The MR lines did not show any negative effects on the main agronomic traits, including yield production and rice grain quality. The lines have significant potential to stabilize rice yield and minimize production costs in disease and pest-prone areas in Korea, through the pyramiding of five R genes using a marker-assisted backcrossing strategy.201829974251
4780160.9845Characterization of two virulent Proteus mirabilis phages and application of phage cocktail in raw chicken safety. Proteus mirabilis is an opportunistic pathogen belonging to the genus Proteus in the Morganellaceae. It is closely associated with infections of the gastrointestinal and urinary systems in humans and animals, posing a threat to the safety of food industries. With the increasing abuse of antibiotics, the problem of bacterial resistance has become extremely urgent. Moreover, animal-source foods often have drug residues, making it an urgent need to explore alternatives to antibiotics. Bacteriophages, bacteria-lysing viruses, cause no biological pollution and do not induce bacterial antibiotic resistance, making them potential green biological bactericides. In this study, 24 pathogenic P. mirabilis strains were isolated as host bacteria. Two virulent bacteriophages, Proteus phage ABTNL-P14 (referred to as P14) and Proteus phage ABTNL-Pp2 (referred to as Pp2), were isolated and identified, both showing effective infectivity against P. mirabilis. Two phages were confirmed as virulent strains lacking virulence factors, lysogeny-related genes and antibiotic resistance genes, meeting safety criteria for food applications. This study also evaluated the effectiveness of a P14 and Pp2 phage cocktail in eliminating P. mirabilis from chicken breast meat at 4 °C under MOIs of 1, 100, and 10,000. Notably, at a high MOI (10,000), the phage cocktail eliminated two host strains on chicken breast meat surfaces within 1 h and 6 h. Therefore, the phage cocktail has the potential to eliminate P. mirabilis in foods at low temperatures, serving as a green antibacterial agent for food applications.202641136136
8176170.9843Overcoming 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
9736180.9843Coevolutionary 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
6280190.9843Genomic variation in Pseudomonas aeruginosa clinical respiratory isolates with de novo resistance to a bacteriophage cocktail. Pseudomonas aeruginosa is an opportunistic pathogen that can cause sinus infections and pneumonia in cystic fibrosis (CF) patients. Bacteriophage therapy is being investigated as a treatment for antibiotic-resistant P. aeruginosa infections. Although virulent bacteriophages have shown promise in treating P. aeruginosa infections, the development of bacteriophage-insensitive mutants (BIMs) in the presence of bacteriophages has been described. The aim of this study was to examine the genetic changes associated with the BIM phenotype. Biofilms of three genetically distinct P. aeruginosa strains, including PAO1 (ATCC 15692), and two clinical respiratory isolates (one CF and one non-CF) were grown for 7 days and treated with either a cocktail of four bacteriophages or a vehicle control for 7 consecutive days. BIMs isolated from the biofilms were detected by streak assays, and resistance to the phage cocktail was confirmed using spot test assays. Comparison of whole genome sequencing between the recovered BIMs and their respective vehicle control-treated phage-sensitive isolates revealed structural variants in two strains, and several small variants in all three strains. These variations involved a TonB-dependent outer membrane receptor in one strain, and mutations in lipopolysaccharide synthesis genes in two strains. Prophage deletion and induction were also noted in two strains, as well as mutations in several genes associated with virulence factors. Mutations in genes involved in susceptibility to conventional antibiotics were also identified in BIMs, with both decreased and increased antibiotic sensitivity to various antibiotics being observed. These findings may have implications for future applications of lytic phage therapy.IMPORTANCELytic bacteriophages are viruses that infect and kill bacteria and can be used to treat difficult-to-treat bacterial infections, including biofilm-associated infections and multidrug-resistant bacteria. Pseudomonas aeruginosa is a bacterium that can cause life-threatening infections. Lytic bacteriophage therapy has been trialed in the treatment of P. aeruginosa infections; however, sometimes bacteria develop resistance to the bacteriophages. This study sheds light on the genetic mechanisms of such resistance, and how this might be harnessed to restore the sensitivity of multidrug-resistant P. aeruginosa to conventional antibiotics.202540162801