Guo-Ying Zuo1, Cui-Xian Yang2, Jun Han3, Yu-Qing Li4, Gen-Chun Wang5. 1. Research Center for Natural Medicines, Kunming General Hospital of Chengdu Military Command, Kunming 650032, China. Electronic address: zuoguoying@263.net. 2. Research Center for Natural Medicines, Kunming General Hospital of Chengdu Military Command, Kunming 650032, China; School of Basic Medical Sciences, Yunnan Traditional Chinese Medical College, Kunming 650500, China. 3. School of Basic Medical Sciences, Yunnan Traditional Chinese Medical College, Kunming 650500, China. Electronic address: hanzjn@126.com. 4. School of Basic Medical Sciences, Yunnan Traditional Chinese Medical College, Kunming 650500, China. 5. Research Center for Natural Medicines, Kunming General Hospital of Chengdu Military Command, Kunming 650032, China.
Abstract
BACKGROUND: Clinical methicillin-resistant Staphylococcus aureus (MRSA) is a thorny problem in current anti-infective therapeutics and a challenge of new drug development. Plant prenylflavonoids possess anti-MRSA activity, but few of the prenylflavonoids have been reported the synergistic anti-MRSA effect when they are used in combination with conventional antibacterial agents. PURPOSE: This study deals with anti-MRSA activity of four prenylflavonoids from the root bark of Morus alba and their synergism with 11 conventional antibacterial agents. METHODS: Chromatographic methods and spectral analysis were used to isolate and identify the prenylflavonoids. The antibacterial activity and synergism were assessed by the broth microdilution method, checkerboard dilution test, and time-kill curve assay, respectively. RESULTS: Four prenylflavonoids, i.e., cyclocommunol (Cy, 1), morusinol (Ml, 2), morusin (Mi, 3) and kuwanon E (Ku, 4), were isolated from Morus alba bark ethanol extract. Compounds 1, 3 and 4 showed high antimicrobial activity on both methicillin-susceptible S. aureus (MSSA) and MRSA strains with MICs/MBCs at 4-16/32-64 and 4-32/16-128 µg/ml, respectively. Ml (2) was not active. Compound 2 showed synergy with amikacin (AK) and streptomycin (SM) against all the ten MRSA isolates. Ml (2) and Ku (4) also showed synergy with ciprofloxacin (CI), etimicin (EM) and vancomycin (VA) against 7-9 isolates. The fractional inhibitory concentration indices (FICIs) ranged 0.09-1.00 and the dose reduction indices (DRIs) of these antibacterial agents ranged 2-128. Cy (1) and Mi (3) showed synergy with the tested antibacterial agents against only 1-3 MRSA isolates except VA. Furthermore, the MRSA resistance could be reversed in the combinations of AK with Cy, Ml, Mi and Ku; EM with Mi and Ku; and SM with Ml by the criteria of MIC interpretive standards for Staphylococcus spp. of CLSI. All the combinations showed only indifference in the 1 × MIC time-killing experiments. The prenylated substitutions play an important role in the activity of the compounds used alone and combined with the tested antibacterials. CONCLUSIONS: The study revealed for the first time the anti-MRSA synergism of prenylflavonoids 1-4 with eleven antibacterial agents and the reversal of MRSA resistance to aminoglycosides, especially amikacin. The results might be valuable for the development of new antibacterial drugs and synergists against MRSA infection.
BACKGROUND: Clinical methicillin-resistant Staphylococcus aureus (MRSA) is a thorny problem in current anti-infective therapeutics and a challenge of new drug development. Plant prenylflavonoids possess anti-MRSA activity, but few of the prenylflavonoids have been reported the synergistic anti-MRSA effect when they are used in combination with conventional antibacterial agents. PURPOSE: This study deals with anti-MRSA activity of four prenylflavonoids from the root bark of Morus alba and their synergism with 11 conventional antibacterial agents. METHODS: Chromatographic methods and spectral analysis were used to isolate and identify the prenylflavonoids. The antibacterial activity and synergism were assessed by the broth microdilution method, checkerboard dilution test, and time-kill curve assay, respectively. RESULTS: Four prenylflavonoids, i.e., cyclocommunol (Cy, 1), morusinol (Ml, 2), morusin (Mi, 3) and kuwanon E (Ku, 4), were isolated from Morus alba bark ethanol extract. Compounds 1, 3 and 4 showed high antimicrobial activity on both methicillin-susceptible S. aureus (MSSA) and MRSA strains with MICs/MBCs at 4-16/32-64 and 4-32/16-128 µg/ml, respectively. Ml (2) was not active. Compound 2 showed synergy with amikacin (AK) and streptomycin (SM) against all the ten MRSA isolates. Ml (2) and Ku (4) also showed synergy with ciprofloxacin (CI), etimicin (EM) and vancomycin (VA) against 7-9 isolates. The fractional inhibitory concentration indices (FICIs) ranged 0.09-1.00 and the dose reduction indices (DRIs) of these antibacterial agents ranged 2-128. Cy (1) and Mi (3) showed synergy with the tested antibacterial agents against only 1-3 MRSA isolates except VA. Furthermore, the MRSA resistance could be reversed in the combinations of AK with Cy, Ml, Mi and Ku; EM with Mi and Ku; and SM with Ml by the criteria of MIC interpretive standards for Staphylococcus spp. of CLSI. All the combinations showed only indifference in the 1 × MIC time-killing experiments. The prenylated substitutions play an important role in the activity of the compounds used alone and combined with the tested antibacterials. CONCLUSIONS: The study revealed for the first time the anti-MRSA synergism of prenylflavonoids 1-4 with eleven antibacterial agents and the reversal of MRSA resistance to aminoglycosides, especially amikacin. The results might be valuable for the development of new antibacterial drugs and synergists against MRSA infection.
Authors: Gina Porras; François Chassagne; James T Lyles; Lewis Marquez; Micah Dettweiler; Akram M Salam; Tharanga Samarakoon; Sarah Shabih; Darya Raschid Farrokhi; Cassandra L Quave Journal: Chem Rev Date: 2020-11-09 Impact factor: 60.622
Authors: Katharina Klose; Eva-Maria Packeiser; Petra Müller; José Luis Granados-Soler; Jan Torben Schille; Sandra Goericke-Pesch; Manfred Kietzmann; Hugo Murua Escobar; Ingo Nolte Journal: PLoS One Date: 2021-09-27 Impact factor: 3.240