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Eradication of drug-resistant Acinetobacter baumannii by cell-penetrating peptide fused endolysin
Lim Jeonghyun,Jang Jaeyeon,Myung Heejoon,Song Miryoung 한국미생물학회 2022 The journal of microbiology Vol.60 No.8
Antimicrobial agents targeting peptidoglycan have shown successful results in eliminating bacteria with high selective toxicity. Bacteriophage encoded endolysin as an alternative antibiotics is a peptidoglycan degrading enzyme with a low rate of resistance. Here, the engineered endolysin was developed to defeat multiple drug-resistant (MDR) Acinetobacter baumannii. First, putative endolysin PA90 was predicted by genome analysis of isolated Pseudomonas phage PBPA. The His-tagged PA90 was purified from BL21(DE3) pLysS and tested for the enzymatic activity using Gram-negative pathogens known for having a high antibiotic resistance rate including A. baumannii. Since the measured activity of PA90 was low, probably due to the outer membrane, cell-penetrating peptide (CPP) DS4.3 was introduced at the N-terminus of PA90 to aid access to its substrate. This engineered endolysin, DS-PA90, completely killed A. baumannii at 0.25 μM, at which concentration PA90 could only eliminate less than one log in CFU/ml. Additionally, DS-PA90 has tolerance to NaCl, where the ~50% of activity could be maintained in the presence of 150 mM NaCl, and stable activity was also observed with changes in pH or temperature. Even MDR A. baumannii strains were highly susceptible to DS-PA90 treatment: five out of nine strains were entirely killed and four strains were reduced by 3–4 log in CFU/ml. Consequently, DS-PA90 could protect waxworm from A. baumannii-induced death by ~70% for ATCC 17978 or ~44% for MDR strain 1656-2 infection. Collectively, our data suggest that CPP-fused endolysin can be an effective antibacterial agent against Gramnegative pathogens regardless of antibiotics resistance mechanisms.
Bactericidal Effect of Cecropin A Fused Endolysin on Drug-Resistant Gram-Negative Pathogens
Lim, Jeonghyun,Hong, Juyeon,Jung, Yongwon,Ha, Jaewon,Kim, Hwan,Myung, Heejoon,Song, Miryoung The Korean Society for Microbiology and Biotechnol 2022 Journal of microbiology and biotechnology Vol.32 No.6
The rapid spread of superbugs leads to the escalation of infectious diseases, which threatens public health. Endolysins derived from bacteriophages are spotlighted as promising alternative antibiotics against multi-drug resistant bacteria. In this study, we isolated and characterized the novel Salmonella typhimurium phage PBST08. Bioinformatics analysis of the PBST08 genome revealed putative endolysin ST01 with a lysozyme-like domain. Since the lytic activity of the purified ST01 was minor, probably owing to the outer membrane, which blocks accessibility to peptidoglycan, antimicrobial peptide cecropin A (CecA) was fused to the N-terminus of ST01 to disrupt the outer membrane. The resulting CecA::ST01 has been shown to have increased bactericidal activity against gram-negative pathogens including Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, and Enterobacter cloacae and the most affected target was A. baumannii. In the presence of 0.25 µM CecA::ST01, A. baumannii ATCC 17978 strain was completely killed and CCARM 12026 strain was wiped out by 0.5 µM CecA::ST01, which is a clinical isolate of A. baumannii and resistant to multiple drugs including carbapenem. Moreover, the larvae of Galleria mellonella could be rescued up to 58% or 49% by the administration of CecA::ST01 upon infection by A. baumannii 17978 or CCARM 12026 strain. Finally, the antibacterial activity of CecA::ST01 was verified using 31 strains of five gram-negative pathogens by evaluation of minimal inhibitory concentration. Thus, the results indicate that a fusion of antimicrobial peptide to endolysin can enhance antibacterial activity and the spectrum of endolysin where multi-drug resistant gram-negative pathogens can be efficiently controlled.
Jeonghyun Park,Eunsoo Moon,Hyun Ju Lim,Kyungwon Kim,Yoo Rha Hong,Jung Hyun Lee 대한정신약물학회 2023 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.21 No.4
Objective: As dopamine is closely linked to locomotor activities, animal studies on locomotor activities using dopaminergic agents were widely done. However, most of animal studies were performed for a short period that there is a lack of longitudinal study on the effects of dopaminergic agents on locomotor activities. This study aimed to examine the longterm effect of a dopamine D2, D3 agonist quinpirole on locomotor activities in mice using a home-cage monitoring system. Methods: The locomotor activities of Institute Cancer Research mice were measured by infrared motion detectors in home-cages under the 12-hour dark and 12-hour light condition for three days after the quinpirole injection. Quinpirole was injected at a concentration of 0.5 mg/kg intraperitoneally in the beginning of the dark phase. The locomotor activities before and after the quinpirole administration were compared by the Wilcoxon signed-rank test and one-way repeated measures ANOVA. Results: After the quinpirole administration, the 24-hour total locomotor activity did not change (p = 0.169), but activities were significantly increased in the 12-hour dark phase sum (p = 0.013) and decreased in the 12-hour light phase sum (p = 0.009). Significant increases in the activities were observed in the dark-light difference (p = 0.005) and dark-light ratio (p = 0.005) as well. Conclusion: This study suggests that quinpirole injection entrains the circadian rest-activity rhythm of locomotor activities. Therefore, quinpirole can be a drug that mediates locomotor activity as a dopamine agonist as well as a modulator of the circadian rhythms.
Lim, Younghyun,Lee, Jeonghyun,Park, Suneui,Jo, Yongwoo,Choi, Jaehyouk IEEE 2018 IEEE journal of solid-state circuits Vol.53 No.9
<P>Herein is presented an external capacitorless low-dropout regulator (LDO) that provides high-power-supply rejection (PSR) at all low-to-high frequencies. The LDO is designed to have the dominant pole at the gate of the pass transistor to secure stability without the use of an external capacitor, even when the load current increases significantly. Using the proposed adaptive supply-ripple cancellation (ASRC) technique, in which the ripples copied from the supply are injected adaptively to the body gate, the PSR hump that appears in conventional gate-pole-dominant LDOs can be suppressed significantly. Since the ASRC circuit continues to adjust the magnitude of the injecting ripples to an optimal value, the LDO presented here can maintain high PSRs, irrespective of the magnitude of the load current <TEX>$I_{L}$</TEX>, or the dropout voltage <TEX>$V_{\mathrm {DO}}$</TEX>. The proposed LDO was fabricated in a 65-nm CMOS process, and it had an input voltage of 1.2 V. With a 240-pF load capacitor, the measured PSRs were less than −36 dB at all frequencies from 10 kHz to 1 GHz, despite changes of <TEX>$I_{L}$</TEX> and <TEX>$V_{\mathrm {DO}}$</TEX> as well as process, voltage, temperature (PVT) variations.</P>