Antibacterial Activity of Squaric Amide Derivative SA2 against Methicillin-Resistant Staphylococcus aureus

• Published in: Antibiotics (Basel) 2022-10, Vol.11 (11), p.1497
• Main Authors: Yu, Moxi, Hou, Yachen, Cheng, Meiling, Liu, Yongshen, Ling, Caise, Zhai, Dongshen, Zhao, Hui, Li, Yaoyao, Chen, Yamiao, Xue, Xiaoyan, Ma, Xue, Jia, Min, Wang, Bin, Wang, Pingan, Li, Mingkai
• Format: Article
• Language: English
• Subjects: Alanine; Alanine dehydrogenase; Animal models; Animal tissues; Antibacterial activity; Antibacterial agents; Antibiotics; Bacteria; Bactericidal activity; Dehydrogenases; Drug resistance; Gram-negative bacteria; Gram-positive bacteria; Health risks; Homeostasis; infection; Infections; Lead compounds; Methicillin; Minimum inhibitory concentration; Nicotinamide adenine dinucleotide; Nosocomial infections; Pathogens; Public health; Scanning electron microscopy; Skin; squaric amide; Staphylococcus aureus; Staphylococcus infections; Strains (organisms); Transcriptomes
• ISSN: 2079-6382; 2079-6382
• DOI: 10.3390/antibiotics11111497

Methicillin-resistant Staphylococcus aureus (MRSA)-caused infection is difficult to treat because of its resistance to commonly used antibiotic, and poses a significant threat to public health. To develop new anti-bacterial agents to combat MRSA-induced infections, we synthesized novel squaric amide derivatives and evaluated their anti-bacterial activity by determining the minimum inhibitory concentration (MIC). Additionally, inhibitory activity of squaric amide 2 (SA2) was measured using the growth curve assay, time-kill assay, and an MRSA-induced skin infection animal model. A scanning electron microscope and transmission electron microscope were utilized to observe the effect of SA2 on the morphologies of MRSA. Transcriptome analysis and real-time PCR were used to test the possible anti-bacterial mechanism of SA2. The results showed that SA2 exerted bactericidal activity against a number of MRSA strains with an MIC at 4–8 µg/mL. It also inhibited the bacterial growth curve of MRSA strains in a dose-dependent manner, and reduced the colony formation unit in 4× MIC within 4–8 h. The infective lesion size and the bacterial number in the MRSA-induced infection tissue of mice were reduced significantly within 7 days after SA2 treatment. Moreover, SA2 disrupted the bacterial membrane and alanine dehydrogenase-dependent NAD+/NADH homeostasis. Our data indicates that SA2 is a possible lead compound for the development of new anti-bacterial agents against MRSA infection.