Bacteriophage-Mediated Risk Pathways Underlying the Emergence of Antimicrobial Resistance via Intrageneric and Intergeneric Recombination of Antibiotic Efflux Genes Across Natural populations of Human Pathogenic Bacteria

Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, Nisar MA, Alvi RF, Aslam MA, Qamar MU, Salamat MKF, Baloch Z (2018) Antibiotic resistance: a rundown of a global crisis. IDR 11:1645–1658. https://doi.org/10.2147/IDR.S173867 Frost I, Van Boeckel TP, Pires J, Craig J, Laxminarayan R (2019) Global geographic trends in antimicrobial resistance: the role of international travel. Journal of Travel Medicine 26:taz036. https://doi.org/10.1093/jtm/taz036 Lerminiaux NA, Cameron ADS (2019) Horizontal transfer of antibiotic resistance genes in clinical environments. Can J Microbiol 65:34–44. https://doi.org/10.1139/cjm-2018-0275 Lynch JP, Clark NM, Zhanel GG (2013) Evolution of antimicrobial resistance among Enterobacteriaceae (focus on extended spectrum β-lactamases and carbapenemases). Expert Opin Pharmacother 14:199–210. https://doi.org/10.1517/14656566.2013.763030 Webber MA (2003) The importance of efflux pumps in bacterial antibiotic resistance. J Antimicrob Chemother 51:9–11. https://doi.org/10.1093/jac/dkg050 Poole K (2007) Efflux pumps as antimicrobial resistance mechanisms. Ann Med 39:162–176. https://doi.org/10.1080/07853890701195262 Nikaido H, Pagès J-M (2012) Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol Rev 36:340–363. https://doi.org/10.1111/j.1574-6976.2011.00290.x Roberts MC (2003) Tetracycline therapy: update. Clin Infect Dis 36:462–467. https://doi.org/10.1086/367622 Peterson E, Kaur P (2018) Antibiotic resistance mechanisms in bacteria: relationships between resistance determinants of antibiotic producers, environmental bacteria, and clinical pathogens. Front Microbiol 9:2928. https://doi.org/10.3389/fmicb.2018.02928 Gabashvili E, Osepashvili M, Koulouris S, Ujmajuridze L, Tskhitishvili Z, Kotetishvili M (2020) Phage transduction is involved in the intergeneric spread of antibiotic resistance-associated blaCTX-M, mel, and tetM Loci in natural populations of some human and animal bacterial pathogens. Curr Microbiol 77:185–193. https://doi.org/10.1007/s00284-019-01817-2 Clokie MRJ, Millard AD, Letarov AV, Heaphy S (2011) Phages in nature Bacteriophage 1:31–45. https://doi.org/10.4161/bact.1.1.14942 Torres-Barceló C (2018) The disparate effects of bacteriophages on antibiotic-resistant bacteria. Emerging Microbes & Infections 7:1–12. https://doi.org/10.1038/s41426-018-0169-z Nadeem SF, Gohar UF, Tahir SF, Mukhtar H, Pornpukdeewattana S, Nukthamna P, Moula Ali AM, Bavisetty SCB, Massa S (2020) Antimicrobial resistance: more than 70 years of war between humans and bacteria. Crit Rev Microbiol 46:578–599. https://doi.org/10.1080/1040841X.2020.1813687 Bushman F (2002) Lateral DNA Transfer: Mechanisms and Consequences. Cold Spring Harbor Laboratory Press, New York Ubukata K, Konno M, Fujii R (1975) Transduction of drug resistance to tetracycline, chloramphenicol, macrolides, lincomycin and clindamycin with phages induced from Streptococcus pyogenes. J Antibiot (Tokyo) 28:681–688. https://doi.org/10.7164/antibiotics.28.681 Fancello L, Desnues C, Raoult D, Rolain JM (2011) Bacteriophages and diffusion of genes encoding antimicrobial resistance in cystic fibrosis sputum microbiota. J Antimicrob Chemother 66:2448–2454. https://doi.org/10.1093/jac/dkr315 Rolain JM, Fancello L, Desnues C, Raoult D (2011) Bacteriophages as vehicles of the resistome in cystic fibrosis. J Antimicrob Chemother 66:2444–2447. https://doi.org/10.1093/jac/dkr318 Moon K, Jeon JH, Kang I, Park KS, Lee K, Cha C-J, Lee SH, Cho J-C (2020) Freshwater viral metagenome reveals novel and functional phage-borne antibiotic resistance genes. Microbiome 8:75. https://doi.org/10.1186/s40168-020-00863-4 Wang GH, Sun BF, Xiong TL, Wang YK, Murfin KE, Xiao JH, Huang DW (2016) Bacteriophage WO can mediate horizontal gene transfer in endosymbiotic wolbachia genomes. Front Microbiol 7:1867. https://doi.org/10.3389/fmicb.2016.01867 Pandey D, Kumari B, Singhal N, Kumar M (2020) BacEffluxPred: a two-tier system to predict and categorize bacterial efflux mediated antibiotic resistance proteins. Sci Rep 10:9287. https://doi.org/10.1038/s41598-020-65981-3 Blum M, Chang H-Y, Chuguransky S, Grego T, Kandasaamy S, Mitchell A, Nuka G, Paysan-Lafosse T, Qureshi M, Raj S, Richardson L, Salazar GA, Williams L, Bork P, Bridge A, Gough J, Haft DH, Letunic I, Marchler-Bauer A, Mi H, Natale DA, Necci M, Orengo CA, Pandurangan AP, Rivoire C, Sigrist CJA, Sillitoe I, Thanki N, Thomas PD, Tosatto SCE, Wu CH, Bateman A, Finn RD (2021) The InterPro protein families and domains database: 20 years on. Nucleic Acids Res 49:D344–D354. https://doi.org/10.1093/nar/gkaa977 Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948. https://doi.org/10.1093/bioinformatics/btm404 Bandelt H-J, Dress AWM (1992) Split decomposition: a new and useful approach to phylogenetic analysis of distance data. Mol Phylogenet Evol 1:242–252. https://doi.org/10.1016/1055-7903(92)90021-8 Martin DP, Murrell B, Golden M, Khoosal A, Muhire B (2015) RDP4: Detection and analysis of recombination patterns in virus genomes. Virus Evolution 1:vev003. https://doi.org/10.1093/ve/vev003 Kosakovsky Pond SL, Posada D, Gravenor MB, Woelk CH, Frost SDW (2006) GARD: a genetic algorithm for recombination detection. Bioinformatics 22:3096–3098. https://doi.org/10.1093/bioinformatics/btl474 Martin D, Rybicki E (2000) RDP: detection of recombination amongst aligned sequences. Bioinformatics 16:562–563. https://doi.org/10.1093/bioinformatics/16.6.562 Padidam M, Sawyer S, Fauquet CM (1999) Possible emergence of new Geminiviruses by frequent recombination. Virology 265:218–225. https://doi.org/10.1006/viro.1999.0056 Martin DP, Posada D, Crandall KA, Williamson C (2005) A modified bootscan algorithm for automated identification of recombinant sequences and recombination breakpoints. AIDS Res Hum Retroviruses 21:98–102. https://doi.org/10.1089/aid.2005.21.98 Smith J (1992) Analyzing the mosaic structure of genes. J Mol Evol 34:126–129. https://doi.org/10.1007/BF00182389 Posada D, Crandall KA (2001) Evaluation of methods for detecting recombination from DNA sequences: Computer simulations. Proc Natl Acad Sci 98:13757–13762. https://doi.org/10.1073/pnas.241370698 Gibbs MJ, Armstrong JS, Gibbs AJ (2000) Sister-Scanning: a Monte Carlo procedure for assessing signals in recombinant sequences. Bioinformatics 16:573–582. https://doi.org/10.1093/bioinformatics/16.7.573 Boni MF, Posada D, Feldman MW (2007) An exact nonparametric method for inferring mosaic structure in sequence triplets. Genetics 176:1035–1047. https://doi.org/10.1534/genetics.106.068874 Bruen TC, Philippe H, Bryant D (2006) A simple and robust statistical test for detecting the presence of recombination. Genetics 172:2665–2681. https://doi.org/10.1534/genetics.105.048975 Zhang F, Zhou F, Gan R, Ren C, Jia Y, Yu L, Huang Z (2019) PHISDetector: a tool to detect diverse in silico phage-host interaction signals for virome studies. bioRxiv 661074. https://doi.org/10.1101/661074 Hockenberry AJ, Wilke CO (2021) BACPHLIP: Predicting bacteriophage lifestyle from conserved protein domains. PeerJ 9:e11396. https://doi.org/10.7717/peerj.11396 McNair K, Bailey BA, Edwards RA (2012) PHACTS, a computational approach to classifying the lifestyle of phages. Bioinformatics 28:614–618. https://doi.org/10.1093/bioinformatics/bts014 Tynecki P, Guziński A, Kazimierczak J, Jadczuk M, Dastych J, Onisko A (2020) PhageAI - Bacteriophage Life Cycle Recognition with Machine Learning and Natural Language Processing. bioRxiv 2020.07.11.198606. https://doi.org/10.1101/2020.07.11.198606 Yuan Y, Gao M, Peng Q, Wu D, Liu P, Wu Y (2014) Genomic analysis of a phage and prophage from a Bacillus thuringiensis strain. J Gen Virol 95:751–761. https://doi.org/10.1099/vir.0.058735-0 Marti E, Variatza E, Balcazar JL (2014) The role of aquatic ecosystems as reservoirs of antibiotic resistance. Trends Microbiol 22:36–41. https://doi.org/10.1016/j.tim.2013.11.001 de Melo AL, A, Soccol VT, Soccol CR, (2016) Bacillus thuringiensis : mechanism of action, resistance, and new applications: a review. Crit Rev Biotechnol 36:317–326. https://doi.org/10.3109/07388551.2014.960793 Arjun R, Niyas VK, Sasidharan A, Palakunnath GA (2020) Streptococcus gallolyticus bacteremia: experience from a tertiary center in south India. Indian J Crit Care Med 24:943–945. https://doi.org/10.5005/jp-journals-10071-23569 Susilawathi NM, Tarini NMA, Fatmawati NND, Mayura PIB, Suryapraba AAA, Subrata M, Sudewi AAR, Mahardika GN (2019) Streptococcus suis –associated meningitis, Bali, Indonesia, 2014–2017. Emerg Infect Dis 25:2235–2242. https://doi.org/10.3201/eid2512.181709 Alav I, Sutton JM, Rahman KM (2018) Role of bacterial efflux pumps in biofilm formation. J Antimicrob Chemother 73:2003–2020. https://doi.org/10.1093/jac/dky042 Byrd AL, Deming C, Cassidy SKB, Harrison OJ, Ng W-I, Conlan S, Comparative Sequencing Program NISC, Belkaid Y, Segre JA, Kong HH (2017) Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis. Sci Transl Med 9:aal4651. https://doi.org/10.1126/scitranslmed.aal4651 Rhodes KA, Schweizer HP (2016) Antibiotic resistance in Burkholderia species. Drug Resist Updates 28:82–90. https://doi.org/10.1016/j.drup.2016.07.003 Solnier J, Martin L, Bhakta S, Bucar F (2020) Flavonoids as novel efflux pump inhibitors and antimicrobials against both environmental and pathogenic intracellular mycobacterial species. Molecules 25:734. https://doi.org/10.3390/molecules25030734 Sutyak Noll K, Sinko PJ, Chikindas ML (2011) Elucidation of the molecular mechanisms of action of the natural antimicrobial peptide subtilosin against the bacterial vaginosis-associated pathogen Gardnerella vaginalis. Probiotics & Antimicro Prot 3:41–47. https://doi.org/10.1007/s12602-010-9061-4 Paulsen IT, Lewis K (2001) Microbial multidrug efflux: introduction. J Mol Microbiol Biotechnol 3:143–144 Orelle C, Mathieu K, Jault J-M (2019) Multidrug ABC transporters in bacteria. Res Microbiol 170:381–391. https://doi.org/10.1016/j.resmic.2019.06.001 Reddy VS, Shlykov MA, Castillo R, Sun EI, Saier MH (2012) The major facilitator superfamily (MFS) revisited: the major facilitator family revisited. FEBS J 279:2022–2035. https://doi.org/10.1111/j.1742-4658.2012.08588.x Smith KP, Kumar S, Varela MF (2009) Identification, cloning, and functional characterization of EmrD-3, a putative multidrug efflux pump of the major facilitator superfamily from Vibrio cholerae O395. Arch Microbiol 191:903–911. https://doi.org/10.1007/s00203-009-0521-8 Putman M, van Veen HW, Konings WN (2000) Molecular properties of bacterial multidrug transporters. Microbiol Mol Biol Rev 64:672–693. https://doi.org/10.1128/MMBR.64.4.672-693.2000 Yu L, Li W, Li Q, Chen X, Ni J, Shang F, Xue T (2020) Role of LsrR in the regulation of antibiotic sensitivity in avian pathogenic Escherichia coli. Poult Sci 99:3675–3687. https://doi.org/10.1016/j.psj.2020.03.064 Bao P, Gao X-L, Wen G-Q (2020) The threat of antibiotics and heavy metal pollution to human health and potential solutions. Biomed Res Int 2020:1–2. https://doi.org/10.1155/2020/8730406 Jebastin T, Narayanan S (2019) In silico epitope identification of unique multidrug resistance proteins from Salmonella Typhi for vaccine development. Comput Biol Chem 78:74–80. https://doi.org/10.1016/j.compbiolchem.2018.11.020 Morita Y, Kataoka A, Shiota S, Mizushima T, Tsuchiya T (2000) NorM of Vibrio parahaemolyticus is an Na+-driven multidrug efflux pump. J Bacteriol 182:6694–6697. https://doi.org/10.1128/JB.182.23.6694-6697.2000 Brown MH, Paulsen IT, Skurray RA (1999) The multidrug efflux protein NorM is a prototype of a new family of transporters. Mol Microbiol 31:394–395. https://doi.org/10.1046/j.1365-2958.1999.01162.x Velamakanni S, Yao Y, Gutmann DAP, van Veen HW (2008) Multidrug transport by the ABC transporter Sav 1866 from Staphylococcus aureus†. Biochemistry 47:9300–9308. https://doi.org/10.1021/bi8006737 Lubelski J, de Jong A, van Merkerk R, Agustiandari H, Kuipers OP, Kok J, Driessen AJM (2006) LmrCD is a major multidrug resistance transporter in Lactococcus lactis. Mol Microbiol 61:771–781. https://doi.org/10.1111/j.1365-2958.2006.05267.x Collins B, Curtis N, Cotter PD, Hill C, Ross RP (2010) The ABC transporter AnrAB contributes to the innate resistance of Listeria monocytogenes to nisin, bacitracin, and various β-lactam antibiotics. AAC 54:4416–4423. https://doi.org/10.1128/AAC.00503-10 Colclough AL, Alav I, Whittle EE, Pugh HL, Darby EM, Legood SW, McNeil HE, Blair JM (2020) RND efflux pumps in Gram-negative bacteria; regulation, structure and role in antibiotic resistance. Future Microbiol 15:143–157. https://doi.org/10.2217/fmb-2019-0235 Li X-Z, Nikaido H (2009) Efflux-mediated drug resistance in bacteria: an update. Drugs 69:1555–1623. https://doi.org/10.2165/11317030-000000000-00000 Dolejska M, Villa L, Poirel L, Nordmann P, Carattoli A (2013) Complete sequencing of an IncHI1 plasmid encoding the carbapenemase NDM-1, the ArmA 16S RNA methylase and a resistance-nodulation-cell division/multidrug efflux pump. J Antimicrob Chemother 68:34–39. https://doi.org/10.1093/jac/dks357 Pasqua G, Zennaro F, Micheli B, Colonna P (2019) The varied role of efflux pumps of the MFS family in the interplay of bacteria with animal and plant cells. Microorganisms 7:285. https://doi.org/10.3390/microorganisms7090285 Pasqua M, Grossi M, Scinicariello S, Aussel L, Barras F, Colonna B, Prosseda G (2019) Author correction: the MFS efflux pump EmrKY contributes to the survival of Shigella within macrophages. Sci Rep 9:7912. https://doi.org/10.1038/s41598-019-44357-2 Grubaugh D, Regeimbal JM, Ghosh P, Zhou Y, Lauer P, Dubensky TW, Higgins DE (2017) The VirAB ABC transporter is required for VirR regulation of Listeria monocytogenes Virulence and resistance to nisin. Infect Immun 86:e00901-17. https://doi.org/10.1128/IAI.00901-17 (/iai/86/3/e00901–17.atom) Penadés JR, Chen J, Quiles-Puchalt N, Carpena N, Novick RP (2015) Bacteriophage-mediated spread of bacterial virulence genes. Curr Opin Microbiol 23:171–178. https://doi.org/10.1016/j.mib.2014.11.019 Brüssow H, Canchaya C, Hardt W-D (2004) Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. MMBR 68:560–602. https://doi.org/10.1128/MMBR.68.3.560-602.2004 Gabashvili E, Kobakhidze S, Koulouris S, Robinson T, Kotetishvili M (2021) Bi- and multi-directional gene transfer in the natural populations of polyvalent bacteriophages, and their host species spectrum representing foodborne versus other human and/or animal pathogens. Food Environ Virol. https://doi.org/10.1007/s12560-021-09460-6