Staphylococcus aureus is a common pathogenic bacterium, and infections caused by S. aureus are seriously threatening public health and safety [1]. Although antibiotics have been highly successful in treating bacterial infectious diseases as routine antimicrobials in current clinical practice, long-term and excessive use of antibiotics leads to severe bacterial resistance and even the development of superbugs [2,3]. Methicillin-resistant S. aureus (MRSA), a typical super-resistant strain, has been listed by the World Health Organization (WHO) as one of the twelve priority pathogens that pose the greatest threat to human health [4,5]. At present, a few clinical drugs such as vancomycin, teicoplanin, and some derivatives of macrolides are available for treating MRSA infections [[6], [7], [8], [9]]. Therefore, there is an urgent need to develop novel antibiotic alternatives to combat MRSA infections.

In recent years, antimicrobial peptides (AMPs) have become a hot topic in the research and development of antimicrobial drugs because of their broad-spectrum antimicrobial effect, specific disruption of bacterial cell membrane mechanisms, ability to rapidly kill bacteria and less susceptible to drug resistance [10,11]. However, with the in-depth research on AMPs, some defects been disclosed for clinical applications, such as low in vivo stability, poor in vivo activity, high toxicity, as well as high manufacturing costs [12,13]. Therefore, to solve inherent defects, several research groups have designed and developed a series of AMP mimetics with membrane activity to mimic the structure and antimicrobial effect of AMPs [[14], [15], [16], [17]].

Natural products (NPs) and their derivatives are an important source for the development of antibiotics [18], such as penicillin G and its derivative amoxicillin (Fig. 1). Isoxanthohumol (1, Fig. 1), one of the most important prenylflavonoids derived mainly from the plant hops (Humulus lupulus L.), has been reported to have various biological activities, including antitumor [19], antioxidant [20,21], anti-inflammatory [22], and antibacterial activities [21,23,24]. Isoxanthohumol (1) is also a metabolite of xanthohumol, which also has antimicrobial activity [25]. It is high in hops, and can be easily synthesized at low cost [25]. Recent studies have shown that isoxanthohumol possesses antibacterial activity against S. aureus (MIC = 50−100 μg/mL) as well as MRSA (MIC = 39 μg/mL) [22,26]. However, there are few studies on the antimicrobial activity of isoxanthohumol derivatives. Here, to improve the antibacterial activity of isoxanthohumol, we envisaged the introduction of some cationic amine groups on the structure of isoxanthohumol to obtain a library of novel isoxanthohumol-amine conjugates as antibacterial agents, drawing on the structural features and biological functions of AMPs (Fig. 1). In the structures of target isoxanthohumol-amine conjugates, isoxanthohumol is an important prenylflavonoid backbone. We hypothesized that the skeleton isoxanthohumol serves as a conformationally rigid hydrophobic core for facilitating insertion into the phospholipid bilayer of bacterial cell membranes, while the positively charged cationic amine groups acts as hydrophilic fraction can facilitate the interaction between the isoxanthohumol-amine conjugates and negatively charged bacterial cell membranes, resulting in alteration of cell membrane permeability or even rupture, thereby killing the bacteria (Fig. 1). Based on this hypothesis, we designed and synthesized a series of isoxanthohumol-amine conjugates and evaluated their antibacterial activities against S. aureus, Escherichia coli and ten clinical MRSA isolates, as well as hemolytic activities against sheep erythrocytes. Subsequently, we further investigated time-kill kinetics, bacterial resistance, antimicrobial mechanism, cytotoxicity, plasma stability, and in vivo safety of the most potent isoxanthohumol derivative. Finally, the in vivo anti-MRSA efficacy of the most promising isoxanthohumol-amine conjugate were evaluated using a mouse skin abscess model infected with MRSA. This work suggests that this design strategy for isoxanthohumol-amine conjugates could provide insights for the development of novel NP-based antimicrobial agents.