A Novel Ivermectin-Derived Compound D4 and Its Antimicrobial/Biofilm Properties against MRSA

• Main Authors: Xinyi Tan, Haoji Xie, Bin Zhang, Jiale Zhou, Zhende Dou, Xiao Wang, Ning Wang
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Antibiotics
• Subjects: ivermectin derivative; MRSA; antibacterial; antibiofilm; mechanisms
• Online Access: https://www.mdpi.com/2079-6382/10/2/208

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and its biofilms infection is still a serious threat to global health. It is urgent to develop efficient drugs by repositioning or designing drugs to solve this problem. In this study, the antibacterial/biofilm activity and mechanisms of ivermectin (D) and its 4′′-position amino substitution derivative (D4) against MRSA were investigated. The minimum inhibitory concentration (MIC) of D was 20 μg/mL, which is four times higher than D4 (MIC = 5 μg/mL). The mechanism research demonstrated that D4 was more potent than D at destroying bacterial cell wall, permeating cell membrane (6.25–36.0% vs 1.92–6.04%) and binding to MRSA genomic DNA. Moreover, after incubation with 10–40 μg/mL D4 for 24 h, the percentages of biofilm decreased by 21.2–92.9%, which was more effective than D (no significant change at 40 μg/mL). The antibiofilm effect is achieved by regulating the expression of related genes (<i>RSH</i>, <i>relQ</i>, <i>rsbU</i>, <i>sigB</i>, <i>spA</i>, and <i>icaD</i>). Additionally, though the higher hemolysis makes D4 a safety risk for intravenous injection, other administration options could be considered as well. Therefore, all the results have indicated that D4 may be a potential candidate compound for the treatment of MRSA and its biofilm infections.