Translating phage therapy into the clinic: Recent accomplishments but continuing challenges

PLoS Biology, Journal Year: 2023, Volume and Issue: 21(5), P. e3002119 - e3002119

Published: May 23, 2023

Phage therapy is a medical form of biological control bacterial infections, one that uses naturally occurring viruses, called bacteriophages or phages, as antibacterial agents. Pioneered over 100 years ago, phage nonetheless currently experiencing resurgence in interest, with growing numbers clinical case studies being published. This renewed enthusiasm due large part to holding promise for providing safe and effective cures infections traditional antibiotics acting alone have been unable clear. Essay introduces basic biology, provides an outline the long history therapy, highlights some advantages using phages agents, overview recent successes. Although has clear potential, it faces biological, regulatory, economic challenges its further implementation more mainstream acceptance.

Language: Английский

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Methicillin Resistant Staphylococcus aureus: Molecular Mechanisms Underlying Drug Resistance Development and Novel Strategies to Combat

Infection and Drug Resistance, Journal Year: 2023, Volume and Issue: Volume 16, P. 7641 - 7662

Published: Dec. 1, 2023

Antimicrobial resistance (AMR) represents a major threat to global health. Infection caused by Methicillin-resistant Staphylococcus aureus (MRSA) is one of the well-recognized public health problem globally. In some regions, as many 90% S. infections are reported be MRSA, which cannot treated with standard antibiotics. WHO reports indicated that MRSA circulating in every province worldwide, significantly increasing risk death 64% compared drug-sensitive forms infection attributed its antibiotic resistance. The emergence and spread antibiotic-resistant strains have contributed increased prevalence both healthcare community settings. methicillin due expression penicillin-binding protein 2a (PBP2a), renders it impervious action β-lactam antibiotics including methicillin. other through production beta-lactamases. Although treatment options for limited, there promising alternatives combat infections. Innovative therapeutic strategies wide range activity modes yet explored. review highlights challenges posed elucidates mechanisms underlying development, explores mitigation strategies. Furthermore, focuses on alternative therapies such bacteriophages, immunotherapy, nanobiotics, antimicrobial peptides, emphasizing their synergistic effects efficacy against MRSA. By examining these approaches, this provides insights into potential tackling combatting escalating AMR. Ultimately, multifaceted approach encompassing conventional novel interventions imperative mitigate impact ensure sustainable future healthcare.

Language: Английский

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Bacteriophage–Host Interactions and the Therapeutic Potential of Bacteriophages

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 478 - 478

Published: March 20, 2024

Healthcare faces a major problem with the increased emergence of antimicrobial resistance due to over-prescribing antibiotics. Bacteriophages may provide solution treatment bacterial infections given their specificity. Enzymes such as endolysins, exolysins, endopeptidases, endosialidases, and depolymerases produced by phages interact surfaces, cell wall components, exopolysaccharides, even destroy biofilms. Enzymatic cleavage host envelope components exposes specific receptors required for phage adhesion. Gram-positive bacteria are susceptible infiltration through peptidoglycan, teichoic acid (WTA), lipoteichoic acids (LTAs), flagella. In Gram-negative bacteria, lipopolysaccharides (LPSs), pili, capsules serve targets. Defense mechanisms used differ include physical barriers (e.g., capsules) or endogenous clustered regularly interspaced palindromic repeat (CRISPR)-associated protein (Cas) systems. Phage proteins stimulate immune responses against pathogens improve antibiotic susceptibility. This review discusses attachment cells, penetration use in infections, limitations therapy. The therapeutic potential phage-derived impact that genomically engineered have summarized.

Language: Английский

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Phage Therapy: Combating Infections with Potential for Evolving from Merely a Treatment for Complications to Targeting Diseases

Frontiers in Microbiology, Journal Year: 2016, Volume and Issue: 7

Published: Sept. 26, 2016

Antimicrobial resistance is considered to be one of the greatest challenges medicine and our civilization. Lack progress in developing new anti-bacterial agents has greatly revived interest using phage therapy combat antibiotic-resistant infections. Although a number clinical trials are underway more planned, realistic perspective registration preparations their entering health market significantly contributing current antimicrobial crisis rather remote. Therefore, addition planning further trials, present approach treatment carried out as experimental (compassionate use) should expanded address growing urgent needs increasing cohorts patients for whom no alternative currently available. During past eleven years center`s operation we have obtained relevant laboratory data which not only confirm safety but also provide important information shedding light on many aspects therapy, its optimization allowing construction most appropriate trials. New biology interactions with immune system suggest that future may evolve from dealing complications targeting diseases. However, studies necessary this promising trend.

Language: Английский

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Bacterial vaginosis: An insight into the prevalence, alternative treatments regimen and it's associated resistance patterns

Microbial Pathogenesis, Journal Year: 2018, Volume and Issue: 127, P. 21 - 30

Published: Nov. 28, 2018

Language: Английский

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Microbe-mediated host defence drives the evolution of reduced pathogen virulence

Nature Communications, Journal Year: 2016, Volume and Issue: 7(1)

Published: Nov. 15, 2016

Abstract Microbes that protect their hosts from pathogens are widespread in nature and attractive disease control agents. Given pathogen adaptation to barriers against infection can drive changes virulence, ‘defensive microbes’ may shape severity. Here we show co-evolving a microbe with host-protective properties ( Enterococcus faecalis ) Staphylococcus aureus within Caenorhabditis elegans drives the evolution of reduced virulence as by-product defensive microbe. Using both genomic phenotypic analyses, discover production fewer iron-scavenging siderophores by reduces fitness underpins decline virulence. These data microbes mechanism resistance determine direction evolution.

Language: Английский

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Overcoming the challenges of phage therapy for industrial aquaculture: A review

Aquaculture, Journal Year: 2019, Volume and Issue: 513, P. 734423 - 734423

Published: Aug. 27, 2019

Language: Английский

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Bacterial biodiversity drives the evolution of CRISPR-based phage resistance

Nature, Journal Year: 2019, Volume and Issue: 574(7779), P. 549 - 552

Published: Oct. 23, 2019

Language: Английский

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The Quest for Novel Antimicrobial Compounds: Emerging Trends in Research, Development, and Technologies

Antibiotics, Journal Year: 2019, Volume and Issue: 8(1), P. 8 - 8

Published: Jan. 24, 2019

Pathogenic antibiotic resistant bacteria pose one of the most important health challenges 21st century. The overuse and abuse antibiotics coupled with natural evolutionary processes has led to this crisis. Only incremental advances in development have occurred over last 30 years. Novel classes molecules, such as engineered antibodies, enhancers, siderophore conjugates, phages, photo-switchable antibiotics, genome editing facilitated by CRISPR/Cas system, are providing new avenues facilitate antimicrobial therapies. informatics revolution is transforming research efforts discover novel antibiotics. explosion nanotechnology micro-engineering driving invention materials, enabling cultivation “uncultivable” microbes creating specific rapid diagnostic technologies. Finally, a revival ecological aspects microbial disease management, growth prebiotics, integrated management based on “One Health” model, provide additional manage These, future scientific technological developments, must be aligned sound policy public awareness address risks posed rising resistance.

Language: Английский

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Diversity-Generating Machines: Genetics of Bacterial Sugar-Coating

Trends in Microbiology, Journal Year: 2018, Volume and Issue: 26(12), P. 1008 - 1021

Published: July 21, 2018

Recent advances in glycobiology emphasise the importance of surface carbohydrates evolution bacterial commensals and pathogens. Epidemiological genomic analyses highlight remarkable diversity adaptability polysaccharides, often driven by horizontal DNA transfer. Functional heterogeneity polysaccharide antigens points to multiple factors which have shaped their diversity. Antigenic is a challenge for conjugate vaccines strive eliminate some diseases, like pneumococcal disease. Bacterial pathogens are surrounded diverse polysaccharides include capsules lipopolysaccharides. These play vital role ecology interactions with environment. Here, we review recent rapid advancements this field, improved our understanding roles, structures, genetics antigens. Genetic loci encoding biosynthesis these may evolved as diversity-generating machines, selection from variety forces, including host immunity, bacteriophages, cell–cell interactions. We argue that high adaptive potential should be taken into account design polysaccharide-targeting medical interventions phage-based therapies. The world bacteria extraordinarily diverse, even most superficial each species alone takes years research. Therefore, though produce extracellular biology production has more exceptions than rules. Nevertheless, cross-sectional look at different reveals many similar characteristics carbohydrate antigens, similarities important implications evolution. Here compare main aspects antigen between antibiotic-resistant global priority defined World Health Organization 2017 (www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed), particularly relation functionality, genetics, phenotypic variation. Bacteria several crucial ability colonise cause Gram-negative lipopolysaccharide (LPS), an component outer cell membrane includes highly variable O-antigen end. Gram-negatives can also additional capsular (CPS), forms layer. Gram-positive synthesise teichoic acids, Gram-negatives, CPS, but they do not LPS. In addition major both exopolysaccharides (EPS), released environment attached cell. All roles lifestyle pathogenesis. Polysaccharide enable evasion immune system shielding complement system, antibodies, or engulfment macrophages [14Roberts I.S. biochemistry bacteria.Annu. Rev. Microbiol. 1996; 50: 285-315Crossref PubMed Scopus (0) Google Scholar]. Consequently, widely recognised virulence determinants [15Achtman M. Pluschke G. Clonal analysis descent among selected Escherichia coli.Annu. 1986; 40: 185-210Crossref Scholar, 16Kahler C.M. et al.The (alpha2–>8)-linked polysialic acid capsule lipooligosaccharide structure contribute serogroup B Neisseria meningitidis resist bactericidal activity normal human serum.Infect. Immun. 1998; 66: 5939-5947PubMed 17Kadioglu A. Streptococcus pneumoniae respiratory colonization disease.Nat. 2008; 6: 288-301Crossref (596) 18Rajagopal L. Understanding regulation group streptococcal factors.Future 2009; 4: 201-221Crossref 19Shon A.S. al.Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: new dangerous breed.Virulence. 2013; 107-118Crossref (234) 20Sukupolvi-Petty S. Haemophilus influenzae Type b hcsA hcsB gene products facilitate transport across essential virulence.J. Bacteriol. 2006; 188: 3870-3877Crossref A brief summary WHO presented Table 1. (Note included it does appear on list; however, encapsulated pathogen capsule-targeting use [21Harrison O.B. al.Description nomenclature locus.Emerg. Infect. Dis. 19: 566-573Crossref (117) Scholar]). escape mucous entrapment, thus affecting transmit [22Nelson A.L. al.Capsule enhances limiting mucus-mediated clearance.Infect. 2007; 75: 83-90Crossref (168) 23Zafar M.A. type amount affect shedding transmission pneumoniae.mBio. 2017; 8 (e00989-17)Crossref (6) LPS, together its external component, O-antigen, plays colonisation protecting hydrophobic antibiotics [24Delcour A.H. Outer permeability antibiotic resistance.Biochim. Biophys. Acta. 1794: 808-816Crossref (443) Scholar], inducing resistance against bacteriophages [25Leon Bastias R. Virulence reduction bacteriophage resistant bacteria.Front. 2015; 343Crossref (30) LPS LOS (lipo-oligosaccharide, without O-antigen) been shown Haemophilus, Neisseria, Campylobacter, Enterobacteriaceae [19Shon 21Harrison 26Zwahlen al.Contribution pathogenicity influenzae: comparative genetically-related strains rats.Microb. Pathog. 1: 465-473Crossref 27Plant al.Lipooligosaccharide contributes steps meningitidis.Infect. 74: 1360-1367Crossref 28Zarantonelli M.L. al.Differential inflammatory response during infection mice.Infect. 5506-5512Crossref 29Louwen sialylated core Campylobacter jejuni determinant epithelial invasion.Infect. 76: 4431-4438Crossref (73) Furthermore, adherence cells [30Aly al.Role binding Staphylococcus aureus nasal cells.J. 1980; 141: 463-465Crossref 31Bravo D. al.Different sugar residues required early Salmonella enterica serovars Typhi Typhimurium cells.Microb. 2011; 70-80Crossref (10) Finally, externally secreted EPS, colanic coli alginate Pseudomonas aeruginosa, basis biofilms – self-produced polymeric matrix enables adhesion surfaces protects colonies environmental dangers, desiccation, antibiotics, [32Okshevsky Meyer R.L. establishment, maintenance perpetuation biofilms.Crit. 41: 341-352Crossref Scholar].Table 1Comparison Antigens Priority Pathogens Need New AntibioticsaMajor need divided three categories according urgency antibiotics: critical, medium priority. critical-priority Enterobacteriacae, only K. E. shown. PS, polysaccharide; LOS, lipo-oligosaccharide; wzy, wzy-dependent; synth, synthase-dependent.SpeciesClassCommon habitatMajor PS antigensDiversityBiosynthesisRefsCRITICALAcinetobacter baumanniiGram−Diverse environmentsCapsule38 serovars, 25 genetic clusterswzy1Hu al.Diversity Acinetobacter baumannii assessed sequencing, development molecular serotyping scheme.PLoS One. 8e70329Crossref (51) ScholarPseudomonas aeruginosaGram−Diverse environmentsO-antigens (2 types)20 serogroupswzy, ABC2Lam J.S. al.Genetic functional aeruginosa lipopolysaccharide.Front. 2: 118Crossref (76) 3Islam S.T. Lam Synthesis via Wzx/Wzy-dependent pathway.Can. J. 2014; 60: 697-716Crossref (52) ScholarKlebsiella pneumoniaeGram−Diverse environmentsCapsule, O-antigen80 K-antigens, O-antigenswzy, ABC4Wyres K.L. al.Identification synthesis whole genome data.Microb. Genom. 2016; 2e000102PubMed ScholarEscherichia coliGram−AnimalsCapsule, O-antigen180 O-antigens, 80 K-antigenswzy, ABC5Whitfield C. Biosynthesis assembly Biochem. 39-68Crossref (538) 6Iguchi al.A complete view cluster.DNA Res. 22: 101-107Crossref (56) ScholarHIGHEnterococcus faeciumGram+AnimalsTeichoic acid, capsule(Understudied)Probably wzy7Thurlow L.R. al.Capsular Enterococcus faecalis contribution CpsF serospecificity.J. 191: 6203-6210Crossref ScholarStaphylococcus aureusGram+AnimalsCapsule11 serotypeswzy8O'Riordan Lee J.C. polysaccharides.Clin. 2004; 17: 218-234Crossref (329) ScholarHelicobacter pyloriGram−Human stomachO-antigenAt least eight typeswzk9Li H. redefinition Helicobacter pylori core-oligosaccharide domains.PLoS 13e1006280Crossref (3) ScholarCampylobacter jejuniGram−AnimalsCapsule, LOS47 serotypes, phase variationABC10Guerry P. al.Campylobacter capsules: vaccines.Front. Cell. 2012; 7Crossref ScholarSalmonella entericabTyphi serovar carries capsule.Gram−Diverse environmentsO-antigen46 ABC11Liu B. al.Structural O basis.FEMS 38: 56-89Crossref (58) ScholarNeisseria gonorrhoeaeGram−HumansLOSLOS variation(none)12Goldberg J.B. Genetics Polysaccharides. Taylor & Francis, 1999Crossref ScholarMEDIUMStreptococcus pneumoniaeGram+Human tractCapsule, acid∼100 serotypeswzy, synth13Bentley S.D. biosynthetic locus all 90 serotypes.PLoS Genet. e31Crossref ScholarHaemophilus influenzaeGram−Human LOSSix variationABC12Goldberg Scholara Major synthase-dependent.b capsule. Open table tab spite length, chain consists relatively small number molecules. polymer biosynthesised ways, large majority cases done one mechanisms: wzy-dependent, ABC-dependent, synthase-dependent pathway (reviewed [5Whitfield 33Schmid al.Bacterial exopolysaccharides: pathways engineering strategies.Front. 496Crossref (59) engage sugar-specific enzymes polysaccharide, specific combination determines structure. There notable architectural similarity chains (particularly wzy-synthesis ABC-synthesis operons) variable, polymer-specific region located middle locus, conserved genes usually transport, assembly, export, sugars (in wzy-synthesised operons wzx wzy genes). typical Figure 1, consequences epidemiological discussed Box 1.Box 1The Future SerotypingEven sequence predictive expressed genotype perfect predictor phenotype two reasons. First, mutations within those alter specificity encoded them, altering biochemical linkage producing serotype. Second, outside influence direct final This public health. With increasing adoption high-throughput sequencing strain characterisation research health labs, silico now largely overtaken standard methods, require specialised reagents expertise. (Table I summarises currently publicly available tools serotyping.) flip side gap serologically-determined genetically-determined widening. Thus, remains important, good complex genotype-phenotype map great challenges (see Outstanding Questions).Table IPublic Tools Silico Serotyping Using Whole-Genome DataaThe list contains listed SR, short-reads; A, assembly.NameSpeciesData inputPrecisionWebsiteRefsPAstPseudomonas aeruginosaSR AEntire locusgithub.com/Sandramses/PAst102Thrane S.W. al.Application whole-genome data O-specific isolates.J. Clin. 54: 1782-1788Crossref (4) ScholarKaptiveKlebsiella pneumoniaeAEntire locuskaptive.holtlab.net4Wyres ScholarSerotypeFinderEscherichia coliSR Awzx/wzy/wzt/wzmcge.cbs.dtu.dk/services/SerotypeFinder103Joensen K.G. al.Rapid easy isolates data.J. 53: 2410-2426Crossref (137) ScholarSRST2 + EcOHE. coliSRwzx/wzy/wzt/wzmgithub.com/katholt/srst2104Ingle D.J. al.In short read identifies limited novel O-loci extensive O:H serotype combinations pathogenic lineages.Microb. 2e000064PubMed ScholarSeqSeroSalmonellaSR locuswww.denglab.info/SeqSero105Zhang al.Salmonella determination utilizing 1685-1692Crossref (69) ScholarSISTRSalmonellaACore geneslfz.corefacility.ca/sistr-app106Yoshida C.E. typing resource (SISTR): open web-accessible tool rapidly subtyping draft salmonella assemblies.PLoS 11e0147101Crossref (35) ScholarPneumoCatStreptococcus locusgithub.com/phe-bioinformatics/PneumoCaT107Kapatai al.Whole development, evaluation verification targets prediction using automated pipeline.PeerJ. 4e2477Crossref (31) ScholarSeroBAS. pneumoniaeSREntire locusgithub.com/sanger-pathogens/seroba108Epping al.SeroBA: 2018: 4Google assembly. Even Questions). strikingly consistent generation antigenic bacteria. monosaccharide serotype-specific means shuffling achieved either inactivation (gene loss), exchange leading (horizontal transfer) help transposable elements observed well studied pneumoniae, coli, [4Wyres 34Aanensen D.M. al.Predicted functions specificities loci.J. 189: 7856-7876Crossref presence flanking regions loci, dexB/aliA galF/gnd Klebsiella, promotes entire homologous recombination, requires homology flanks. Such changes serotype/antigen alterations distant lineages having 'invent' combination, documented studies [35Kroll Moxon E.R. Capsulation distantly related b: drift transfer capsulation locus.J. 1990; 172: 1374-1379Crossref (48) 36Achtman al.Multilocus replacement enterica.PLoS 8e1002776Crossref (211) 37Alqasim al.Comparative few traits unique ST131 H30Rx clade mosaicism locus.BMC Genomics. 15: 830Crossref 38Thrane widespread multidrug-resistant O12 clone emerged through concomitant clusters.mBio. 6 (e01396-01315)Crossref (11) 39Croucher N.J. al.Selective constraints switching.PLoS 11e1005095Crossref (24) 40Holt K.E. al.Genomic diversity, population structure, virulence, antimicrobial urgent threat health.Proc. Natl. Acad. Sci. U. 112: E3574-E3581Crossref (171) 41Holt al.Five decades globally distributed, extensively 1.Microb. 2e000052PubMed 42Neemuchwala switching other large-scale recombination events invasive 1 Group Streptococcus.Emerg. 1941-1944Crossref (5) 43Perrin al.Evolutionary dynamics features Elizabethkingia anophelis 2015 2016 Wisconsin outbreak strain.Nat. Commun. 8: 15483Crossref Third, epigenetic regulatory (commonly referred 'phase variation') expression, resulting infect [44Hammerschmidt variation slipped-strand mispairing polysialyltransferase (siaD): correlation invasion meningococcal disease.Mol. 20: 1211-1220Crossref (182) 45Weiser J.N. al.Relationship colony morphology, intrastrain wall physiology, nasopharyngeal pneumoniae.Infect. 64: 2240-2245Crossref robust protein because housekeeping functions, monosaccharides unlike proteins disrupted single amino changes. much flexible changing ability, modifications unlikely incur fitness cost organism. evident successful persistence lost [46Dolan-Livengood J.M. nongroupable meningitidis.J. 2003; 187: 1616-1628Crossref 47Chewapreecha al.Dense sampling highways recombination.Nat. 46: 305-309Crossref loss historical, vitro passaged 48Hobman J.L. al.Laboratory coli: model citizens deceitful delinquents growing old disgracefully?.Mol. 881-885Crossref evidence therefore universally weapons, able diversify speeds [49Moxon al.Adaptive mutable bacteria.Curr. Biol. 1994; 24-33Abstract Full Text PDF Over timescales, produced populations variation; over intermediate timescales serotypes exchanged recombinational spanning loci; long gain novel, combinations, giving rise serotypes. allow adaptation constantly selective pressures, thereby maintaining relative competing species. plasticity give serological types 1), obvious why such arose first place. Arguably, simplest explanation randomly generated time, driving evolutionary force. sheer greater expected based rest 50Mavroidi relatedness 7841-7855Crossref (78) Scholar] undoubtedly suggests diversifying generating structures. existence supported fact variability hotspots close gut [51Zhu al.Inter-individual differences content species.Genome 16: 82Crossref (43) hotspots, [41Holt 52Swartley meningitidis.Proc. 1997; 94: 271-276Crossref 53Milkman al.Molecular chromosome. VI. Two effective recombination.Genetics. 163: 475-483PubMed 54Croucher al.Population genomics post-vaccine epidemiology.Nat. 45: 656-663Crossref (158) 55Wyres al.Pneumococcal switching: historical perspective.J. 207: 439-449Crossref (77) 56Mostowy R.J. cps hotspot gener

Language: Английский

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