CN-116284253-B - Antibacterial peptide targeting staphylococcus aureus and having dual functions of inhibiting quorum sensing signals and antibacterial actions

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to an antibacterial peptide which targets staphylococcus aureus and has double functions of inhibiting quorum sensing signals and resisting bacteria. The invention firstly synthesizes a sultone-free AIP-III variant CP7 with targeting and QS signal path inhibiting in staphylococcus aureus cells, synthesizes FP13-2 antibacterial peptide with broad-spectrum antibacterial activity, and then successfully synthesizes a compound peptide containing a CP7 structural domain and a FP13-2 structural domain. The compound peptide disclosed by the invention can be used for targeted killing of staphylococcus aureus, is also effective on methicillin-resistant staphylococcus aureus, and has higher antibacterial activity and moderate toxicity as shown in vivo and in vitro. In addition, the action mechanism of the compound peptide is different from that of the traditional antibiotics, so that the compound peptide is not easy to generate drug resistance, and a certain guiding value is provided for treating staphylococcus aureus infection and drug-resistant bacteria.

Inventors

• HE JIAN
• LIN HAIXING

Assignees

• 南方医科大学

Dates

Publication Date

20260508

Application Date

20230428

Claims (5)

1. 1. The antibacterial peptide is CP7-FP13-2, and the amino acid sequence of the antibacterial peptide is shown as (L-L-F-A-Dab) -N-I-G-G-C-6MA-G-I-K-N-L-W-K-K-M-I-K-L-W-Y.
2. 2. The use of the antibacterial peptide of claim 1 for the preparation of a medicament for inhibiting staphylococcus aureus.
3. 3. The use of the antibacterial peptide according to claim 1 for the preparation of a medicament for the treatment of staphylococcus aureus infectious diseases.
4. 4. The use according to claim 2 or 3, wherein the medicament further comprises a pharmaceutically acceptable carrier.
5. 5. The use according to claim 2 or 3, wherein the pharmaceutical dosage form comprises injection, tablet, granule, capsule, dripping pill, sustained release preparation, oral liquid, ointment, patch.

Description

Antibacterial peptide targeting staphylococcus aureus and having dual functions of inhibiting quorum sensing signals and antibacterial actions Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to an antibacterial peptide which targets staphylococcus aureus and has double functions of inhibiting quorum sensing signals and resisting bacteria. Background The gram positive bacterium staphylococcus aureus (Staphylococcus aureus, s.aureus) is a common colonizing bacteria for human hosts. It is the most common pathogen in clinical infections and can cause systemic transmission in humans and animals, such as skin and soft tissue infections, urinary tract infections, pneumonia, osteomyelitis, endocarditis, and the like. In recent years, antibiotic resistance has become increasingly common. To address this impending global infection crisis, there is a strong need to explore alternative methods of treating staphylococcus aureus infections with different mechanisms. In addition to obtaining resistance genes, staphylococcus aureus can synthesize several virulence factors and produce biofilms, closely related to bacterial resistance and pathogenicity of staphylococcus aureus. Virulence factors and biofilm formation are tightly controlled by the accessory gene regulatory factor (agr) system, which is found in almost all staphylococci. The agr system is the main regulator of the staphylococcus aureus Quorum Sensing (QS) system, controlling the expression of foreign and surface proteins. The system consists of RNAII and RNAIII transcription units under the control of the P2 promoter and the P3 promoter, respectively. Wherein the P2 operon modulates a four gene operon agrBDCA which biosynthesizes self-induced peptides (AIPs) and processes AgrC and AgrA proteins. The P3 operon drives the expression of RNAIII units, the primary effector of Staphylococcus aureus expression virulence factors. Staphylococcus aureus detects the extracellular self-inducing peptide of bacteria by the AgrC system, thereby mediating the bacterial agr system to control its virulence factors. Up to now, four specific agr groups have been identified in staphylococcus aureus with different AIP (I-IV) sequences, based on the agr operon. Binding of homologous AIP to AgrC activates the agr response and induces virulence factors through the regulatory factors of RNAIII, whereas non-homologous AIP competitively binds to AgrC to inhibit the agr response while still allowing bacterial growth. Thus, variants of AIPs that inhibit the production of AgrC receptors and related staphylococcus aureus toxins are of interest as new strategies against staphylococcus aureus and related infections. Natural antimicrobial peptides (AMPs) are endogenous defenses in the innate immune system that protect the host against a variety of pathogenic agents. Moreover, drug resistance is not easy to occur. Therefore, the development of methods for treating staphylococcus aureus infections based on AIPs variants and natural antimicrobial peptides has important application value. Disclosure of Invention In order to overcome the defects in the prior art, the invention designs an AIP-III variant named CP7, which is combined with a transmembrane protein AgrC extra-loop-II domain in staphylococcus aureus type I and can weaken the expression of a staphylococcus aureus virulence factor in a non-biocidal manner, simultaneously designs and identifies FP (Fusogenic Peptides) with powerful antibacterial activity, and finally successfully constructs a CP7-FP13-2 composite peptide containing a CP7 targeted agr system domain and an FP13-2 broad-spectrum antibacterial domain based on CP7 and FP. In order to achieve the above purpose, the present invention is realized by the following technical scheme: In A first aspect, the invention provides an antimicrobial peptide, which is CP7-FP13-2, and the amino acid sequence of the antimicrobial peptide is shown as (L-L-F-A-Dab) -N-I-G-G-C-6MA-G-I-K-N-L-W-K-K-M-I-K-L-W-Y. The structural formula of CP7-FP13-2 is shown below: The invention firstly designs an AIP-III variant named CP7, which is combined with a transmembrane protein AgrC extra-loop-II domain in staphylococcus aureus type I, and can weaken the expression of a staphylococcus aureus virulence factor in a non-biocidal mode. Meanwhile, based on the previous study of the subject group, several potent AMPs(Wu,W.;Lin,D.;Shen,X.et al.New influenza A Virus Entry Inhibitors Derived from the Viral Fusion Peptides.PLoS One 2015,10(9),e0138426.DOI:10.1371/journal.pone.0138426). were generated here by replacing negatively charged or neutral FP residues with positively charged lysines, based on which the antimicrobial peptide FP13-2 consisting of 13 amino acids was designed with fewer amino acid residues, but still possessing potent antimicrobial activity, including anti-MRSA activity. Finally, the two N ends of the CP7 and the FP13-2 are connected thro