The therapeutic effect of chlorogenic acid against Staphylococcus aureus infection through sortase A inhibition

Abstract

The emergence and wide spread of multi-drug resistant Staphylococcus aureus (S. aureus) requires the development of new therapeutic agents with alternative modes of action. Anti-virulence strategies are hoped to meet that need. Sortase A (SrtA) has attracted great interest as a potential drug target to treat infections caused by S. aureus, as many of the surface proteins displayed by SrtA function as virulence factors by mediating bacterial adhesion to specific organ tissues, invasion of host cells, and evasion of the host-immune responses. It has been suggested that inhibitors of SrtA might be promising candidates for the treatment and/or prevention of S. aureus infections. In this study, we report that chlorogenic acid (CHA), a natural compound that lacks significant anti-S. aureus activity, inhibit the activity of SrtA in vitro (IC50 = 33.86 ± 5.55 μg/ml) and the binding of S. aureus to fibrinogen (Fg). Using molecular dynamics simulations and mutagenesis assays, we further demonstrate that CHA binds to the binding sites of C184 and G192 in the SrtA. In vivo studies demonstrated that CHA prevent mice from S. aureus-induced renal abscess, resulting in a significant survival advantage. These findings indicate that CHA is a promising therapeutic compound against SrtA during S. aureus infections.

Chinese herb medicine against Sortase A catalyzed transformations, a key role in gram-positive bacterial infection progress

“…Berberine chloride is one type of isoquinoline alkaloid (Table 3, Figure 5), from the rhizomes of Coptis chinensis Franch appeared a potent inhibitory effect on SrtA, with an IC 50 value of 8.7 mg/ml and also had antibacterial activity against Gram-positive bacteria, with a MIC more than 100 mg/ml, made a comparison to available isoquinoline alkaloids berberine sulfate, palmatine chloride, and b-hydrastine, which are all antibacterial substances 12 . As previously revealed, similar to curcumin, the aromatic rings of berberine chloride could combine to the hydrophobic side chains (the side chains of from the b6/b7 loop) through hydrophobic effect, embedded into the active site of SrtA, thus inhibiting SrtA activities 104 . In addition, the nitrile group of Berberine chloride can form a hydrogen bond with SrtA catalytic residue Arg 197 via hydrogen bonding 102 .…”

“…In addition, the hydroxyl group of the cyclohexane could also form another hydrogen bond with the backbone carbonyl of Gly 192 and keeps the b7/b8 loop in a closed state. Moreover, the glucopyranoside side chain moiety was found to be the active component of the compound because elimination of this side chain moiety led to a reduction in inhibitory activity 103 , probably also because OH of the cyclohexane moiety of the glucopyranoside side chain moiety can form hydrogen bonds with Arg 197 104 , both of which are important for Cysteine to complete the catalytic process. Hence, we can find out whether other CHMs containing sterol glycoside compounds can inhibit the activity of SrtA, which can provide one approach to find more herbs to inhibit SrtA, in addition figure out whether several kinds of CHMs taken together can strengthen inhibitory activities on SrtA.…”

“…In addition, trytanthrin, another compound in the extract of Radix isatidis, is an isoquinoline type alkaloid. The aromatic rings in aaptamines, as hydrophobic groups, can combine to the hydrophobic side and occupy the sorting signal recognition region through hydrophobic interactions with the side chains from the b6/b7 loop 104 (Figure 5), preventing LPXTGcontaining proteins' combination with SrtA, while the amide carbonyl, NH groups and the oxygen atom in aaptamines, can link to Cys 184 , leading to a failure of the amide bond between SrtA and LPXTG-containing proteins. According to the research about aaptamines, trytanthrin probably can inhibit the activity of SrtA.…”

“…In addition, two aromatic ring of curcumin are located in the trans orientation, similar to the structural formula of (Z)-3-(2,5-dimethoxyphenyl)-2-(4-methoxyphenyl) acrylonitrile (DMMA), one proved inhibitor of SrtA 102,137 . Besides, the aromatic ring could form hydrophobic interactions with the side chains of residues from the b6/b7 loop (Val 169 , Leu 168 ) and Arg 197 , occupying the sorting signal recognition region of SrtA 104 (Figure 1). In conclusion, curcumin of Curcuma longa, as an inhibitor of SrtA, maybe interdict the catalysis process of SrtA by embedding the two aromatic rings into its active site through hydrophobic interaction 111 and forming hydrogen bonds, and as a result, LPXTG-containing proteins can't combine to cell wall of the bacteria by SrtA.…”

“…, resulting in SrtA activity weakened, and thus failing in intermediate product formation (SrtA-T-surface protein). Moreover, the aromatic rings could also interact with the side chains and combine to the hydrophobic active site of SrtA, occupying the sorting signal recognition region of SrtA 104 .…”