Dataset Information

Characterization of the Bacteriophage BUCT603 and Therapeutic Potential Evaluation Against Drug-Resistant Stenotrophomonas maltophilia in a Mouse Model.

ABSTRACT: Stenotrophomonas maltophilia (S. maltophilia) is a common opportunistic pathogen that is resistant to many antibiotics. Bacteriophages are considered to be an effective alternative to antibiotics for the treatment of drug-resistant bacterial infections. In this study, we isolated and characterized a phage, BUCT603, infecting drug-resistant S. maltophilia. Genome sequencing showed BUCT603 genome was composed of 44,912 bp (32.5% G + C content) with 64 predicted open reading frames (ORFs), whereas no virulence-related genes, antibiotic-resistant genes or tRNA were identified. Whole-genome alignments showed BUCT603 shared 1% homology with other phages in the National Center for Biotechnology Information (NCBI) database, and a phylogenetic analysis indicated BUCT603 can be classified as a new member of the Siphoviridae family. Bacteriophage BUCT603 infected 10 of 15 S. maltophilia and used the TonB protein as an adsorption receptor. BUCT603 also inhibited the growth of the host bacterium within 1 h in vitro and effectively increased the survival rate of infected mice in a mouse model. These findings suggest that bacteriophage BUCT603 has potential for development as a candidate treatment of S. maltophilia infection.

SUBMITTER: Han P

PROVIDER: S-EPMC9294509 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Characterization of the Bacteriophage BUCT603 and Therapeutic Potential Evaluation Against Drug-Resistant Stenotrophomonas maltophilia in a Mouse Model.

Han Pengjun P Zhang Wenjing W Pu Mingfang M Li Yahao Y Song Lihua L An Xiaoping X Li Mengzhe M Li Fei F Zhang Shuyan S Fan Huahao H Tong Yigang Y

Frontiers in microbiology 20220705

Stenotrophomonas maltophilia (S. maltophilia) is a common opportunistic pathogen that is resistant to many antibiotics. Bacteriophages are considered to be an effective alternative to antibiotics for the treatment of drug-resistant bacterial infections. In this study, we isolated and characterized a phage, BUCT603, infecting drug-resistant S. maltophilia. Genome sequencing showed BUCT603 genome was composed of 44,912 bp (32.5% G + C content) with 64 predicted open reading fr ...[more]

PMID: 35865914

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Project description:Stenotrophomonas maltophilia is a multidrug resistant pathogen associated with high mortality and morbidity in patients having compromised immunity. The efflux systems of S. maltophilia include SmeABC and SmeDEF proteins, which assist in acquisition of multiple-drug-resistance. In this study, proteome based mapping was utilized to find out the potential drug targets for S. maltophilia strain k279a. Various tools of computational biology were applied to remove the human-specific homologous and pathogen-specific paralogous sequences from the bacterial proteome. The CD-HIT analysis selected 4315 proteins from total proteome count of 4365 proteins. Geptop identified 407 essential proteins, while the BlastP revealed approximately 85 non-homologous proteins in the human genome. Moreover, metabolic pathway and subcellular location analysis were performed for essential bacterial genes, to describe their role in various cellular processes. Only two essential proteins (Acyl-[acyl-carrier-protein]-UDP-N acetyl glucosamine O-acyltransferase and D-alanine-D-alanine ligase) as candidate for potent targets were found in proteome of the pathogen, in order to design new drugs. An online tool, Swiss model was employed to model the 3D structures of both target proteins. A library of 5000 phytochemicals was docked against those proteins through the molecular operating environment (MOE). That resulted in to eight inhibitors for both proteins i.e. enterodiol, aloin, ononin and rhinacanthinF for the Acyl-[acyl-carrier-protein]-UDP-N acetyl glucosamine O-acyltransferase, and rhazin, alkannin beta, aloesin and ancistrocladine for the D-alanine-D-alanine ligase. Finally the ADMET was done through ADMETsar. This study supported the development of natural as well as cost-effective drugs against S. maltophilia. These inhibitors displayed the effective binding interactions and safe drug profiles. However, further in vivo and in vitro validation experiment might be performed to check their drug effectiveness, biocompatibility and their role as effective inhibitors.

Project description:Phage therapy has become a viable antimicrobial treatment as an alternative to antibiotic treatment, with an increase in antibiotic resistance. Phage resistance is a major limitation in the therapeutic application of phages, and the lack of understanding of the dynamic changes between bacteria and phages constrains our response strategies to phage resistance. In this study, we investigated the changing trends of mutual resistance between Stenotrophomonas maltophilia (S. maltophilia) and its lytic phage, BUCT603. Our results revealed that S. maltophilia resisted phage infection through mutations in the cell membrane proteins, while the evolved phage re-infected the resistant strain primarily through mutations in structure-related proteins. Compared with the wild-type strain (SMA118), the evolved phage-resistant strain (R118-2) showed reduced virulence, weakened biofilm formation ability, and reduced resistance to aminoglycosides. In addition, the evolved phage BUCT603B1 in combination with kanamycin could inhibit the development of phage-resistant S. maltophilia in vitro and significantly improve the survival rate of S. maltophilia-infected mice. Altogether, these results suggest that in vitro characterization of bacteria-phage co-evolutionary relationships is a useful research tool to optimize phages for the treatment of drug-resistant bacterial infections.IMPORTANCEPhage therapy is a promising approach to treat infections caused by drug-resistant Stenotrophomonas maltophilia (S. maltophilia). However, the rapid development of phage resistance has hindered the therapeutic application of phages. In vitro evolutionary studies of bacteria-phage co-cultures can elucidate the mechanism of resistance development between phage and its host. In this study, we investigated the resistance trends between S. maltophilia and its phage and found that inhibition of phage adsorption is the primary strategy by which bacteria resist phage infection in vitro, while phages can re-infect bacterial cells by identifying other adsorption receptors. Although the final bacterial mutants were no longer infected by phages, they incurred a fitness cost that resulted in a significant reduction in virulence. In addition, the combination treatment with phage and aminoglycoside antibiotics could prevent the development of phage resistance in S. maltophilia in vitro. These findings contribute to increasing the understanding of the co-evolutionary relationships between phages and S. maltophilia.

Project description:In recent years, Stenotrophomonas maltophilia (S. maltophilia) has become an important pathogen of clinically acquired infections accompanied by high pathogenicity and high mortality. Moreover, infections caused by multidrug-resistant S. maltophilia have emerged as a serious challenge in clinical practice. Bacteriophages are considered a promising alternative for the treatment of S. maltophilia infections due to their unique antibacterial mechanism and superior bactericidal ability compared with traditional antibiotic agents. Here, we reported a new phage BUCT700 that has a double-stranded DNA genome of 43,214 bp with 70% GC content. A total of 55 ORFs and no virulence or antimicrobial resistance genes were annotated in the genome of phage BUCT700. Phage BUCT700 has a broad host range (28/43) and can lyse multiple ST types of clinical S. maltophilia (21/33). Furthermore, bacteriophage BUCT700 used the Type IV fimbrial biogenesis protein PilX as an adsorption receptor. In the stability test, phage BUCT700 showed excellent thermal stability (4 to 60°C) and pH tolerance (pH = 4 to 12). Moreover, phage BUCT700 was able to maintain a high titer during long-term storage. The adsorption curve and one-step growth curve showed that phage BUCT700 could rapidly adsorb to the surface of S. maltophilia and produce a significant number of phage virions. In vivo, BUCT700 significantly increased the survival rate of S. maltophilia-infected Galleria mellonella (G. mellonella) larvae from 0% to 100% within 72 h, especially in the prophylactic model. In conclusion, these findings indicate that phage BUCT700 has promising potential for clinical application either as a prophylactic or therapeutic agent. IMPORTANCE The risk of Stenotrophomonas maltophilia infections mediated by the medical devices is exacerbated with an increase in the number of ICU patients during the Corona Virus Disease 2019 (COVID-19) epidemic. Complications caused by S. maltophilia infections could complicate the state of an illness, greatly extending the length of hospitalization and increasing the financial burden. Phage therapy might be a potential and promising alternative for clinical treatment of multidrug-resistant bacterial infections. Here, we investigated the protective effects of phage BUCT700 as prophylactic and therapeutic agents in Galleria mellonella models of infection, respectively. This study demonstrates that phage therapy can provide protection in targeting S. maltophilia-related infection, especially as prophylaxis.

Dataset Information

Characterization of the Bacteriophage BUCT603 and Therapeutic Potential Evaluation Against Drug-Resistant Stenotrophomonas maltophilia in a Mouse Model.

Publications

Characterization of the Bacteriophage BUCT603 and Therapeutic Potential Evaluation Against Drug-Resistant <i>Stenotrophomonas maltophilia</i> in a Mouse Model.

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