An activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal markers and its application.

Abstract

This invention discloses an activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling and its application. The activated water-soluble photodynamic antibacterial agent of this invention contains hydrophilic groups, which can prevent uptake by normal cells, thereby reducing phototoxicity to normal tissues. In addition, the activated water-soluble photodynamic antibacterial agent of this invention is modified with bioorthogonal reactive groups that can quench the fluorescence and ROS generation capabilities of photosensitizers. This allows for rapid click chemistry reactions with active groups inserted into peptidoglycans during bacterial metabolism, achieving specific labeling and in-situ activation of the photosensitizer on the bacterial surface. Under near-infrared light irradiation, the photodynamic antibacterial agent specifically modified on the bacterial surface can generate a large amount of reactive oxygen species, selectively killing bacteria while avoiding damage to normal tissues, exhibiting broad-spectrum antibacterial activity and showing promising application prospects in photodynamic antibacterial therapy.

Description

Technical Field

[0001] This invention belongs to the technical field of photodynamic antibacterial agents, and more specifically, relates to an activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling and its application. Background Technology

[0002] Bacterial infections have gradually become one of the major threats to human health. Currently, oral and intravenous antibiotics are the most commonly used methods for treating bacterial infections. However, the overuse and misuse of antibiotics have led to a surge in drug-resistant bacteria, significantly reducing clinical treatment effectiveness. Healthcare professionals are forced to use more potent antibiotics, which further increases the risk of adverse drug reactions and medical complications. Furthermore, the discovery of antibiotics with new modes of action is far outpaced by the development of bacterial resistance, and in the long run, humanity will face a situation where no effective drugs are available. Given the serious threat posed by bacteria to human health and the ineffectiveness of traditional antibiotics, we must re-examine the future direction of anti-infective therapy and explore new and effective antibacterial drugs or treatment methods beyond antibiotics.

[0003] Photodynamic therapy (PDT) utilizes photosensitizers to generate reactive oxygen species (ROS) under irradiation with light of appropriate wavelengths (typically from visible to near-infrared). This ROS induces oxidative damage to proteins, lipids, and nucleic acids, leading to metabolic dysfunction and ultimately killing bacteria. PDT has attracted widespread scientific attention and has been applied clinically to treat refractory local infections such as oral bacterial infections and chronic wounds. As a promising non-antibiotic antibacterial strategy, PDT has achieved significant results in addressing bacterial-associated infectious diseases. However, because most photosensitizers have lower selectivity for microorganisms than for host tissues, and because the highly reactive ROS in PDT have short lifespans and release distances within biological systems, the main challenge in using PDT to treat bacterial infections lies in achieving specific targeting of photosensitizers to bacteria while minimizing the side effects of phototherapy.

[0004] Bioorthogonal labeling has become a promising tool for targeting bacteria due to its high sensitivity and specificity. Since bacterial cell walls contain D-amino acid motifs, chemically active groups can be inserted into bacterial peptidoglycans via the metabolic processes of non-natural metabolic precursors (functionalized D-amino acids). The bacterial wall can then be effectively labeled through a click reaction between the chemically active group and its corresponding bioorthogonally modified photosensitizer. Because D-amino acids are generally not present in mammalian cells, this strategy has unique advantages in bacterial targeting and in vivo therapy. However, the "always-on" state of most photosensitizers and their easy uptake by normal cells lead to unavoidable side effects on normal tissues, greatly limiting their practical application. Therefore, there is a need to design and synthesize activated photosensitizers that satisfy bioorthogonal reactions, have well-defined chemical structures, good hydrophilicity, and specific bactericidal effects. Summary of the Invention

[0005] The purpose of this invention is to provide an activated, water-soluble, photodynamic antibacterial agent based on bacterial bioorthogonal labeling. This type of photosensitizer is modified with a click-chemically reactive group. This group can quench the fluorescence and ROS-generating ability of the photosensitizer, but this quenching effect can be reversed by a rapid click-chemical reaction with the reactive group inserted on bacterial peptidoglycan, achieving specific labeling and in-situ activation of the photosensitizer on the bacterial surface. Furthermore, this type of photosensitizer exhibits good solubility in aqueous systems and strong absorption in the near-infrared region, further avoiding phototoxicity to normal tissues and laying a solid foundation for its in vivo application.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] An activated, water-soluble, photodynamic antibacterial agent based on bacterial bioorthogonal labeling is a BODIPY-based compound represented by Formula I:

[0008]

[0009] R1 is a tetrazine click chemical reactive group with fluorescence and photodynamic quenching effects:

[0010]

[0011] R2 is a halogen atom, such as Cl, Br, or I;

[0012] R3 is a hydrophilic modifying group:

[0013] In this invention, R1 preferably has the following groups: The preferred halogen atom of R2 is I;

[0014] R3 is preferably composed of the following groups:

[0015] The activated water-soluble photodynamic antibacterial agent has the following structure:

[0016]

[0017]

[0018] The aforementioned activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling, wherein the introduction of iodine atoms has the highest singlet oxygen generation efficiency.

[0019] The aforementioned activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling, wherein the activated water-soluble photodynamic antibacterial agent has an absorption wavelength of 600-650 nm.

[0020] The aforementioned activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling, wherein the emission wavelength of the activated water-soluble photodynamic antibacterial agent is 650-700nm.

[0021] The aforementioned activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal markers, wherein the activated water-soluble photodynamic antibacterial agent can avoid being taken up by normal cells, thereby reducing phototoxicity to normal tissues.

[0022] The aforementioned activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling is modified with a tetrazine click chemistry reactive group, which can quench the fluorescence and ROS generation capabilities of the photosensitizer. However, upon reaching the bacterial infection site, this quenching effect can be reversed through a rapid click chemistry reaction with an active group (trans-cyclooctene-D-lysine, TCOK) inserted on the bacterial peptidoglycan, thus achieving specific labeling and activation of the photosensitizer on the bacterial surface.

[0023] The aforementioned activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling, wherein, after being specifically labeled and activated on the bacterial surface, the activated water-soluble photodynamic antibacterial agent can selectively kill bacteria under near-infrared light irradiation without damaging normal tissue.

[0024] The aforementioned activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling comprises the following synthesis steps: First, a BODIPY core with an R1 group is synthesized; then, halogen atoms are introduced at positions 2 and 6 of the core for substitution; finally, the core at positions 3 and 5 is modified with a hydrophilic aromatic aldehyde via a Knoevenagel condensation reaction to obtain the activated hydrophilic photodynamic antibacterial agent.

[0025] The aforementioned activated water-soluble photodynamic antibacterial agent based on bacterial bioorthogonal labeling, wherein the compound and its pharmaceutically acceptable salts or solvates are used in the treatment of bacterial infections, including but not limited to oral bacterial infections, wound bacterial infections, and Helicobacter pylori infections.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The activated water-soluble photodynamic antibacterial agent provided by this invention possesses bacterial-specific recognition and activation functions: Utilizing the differences in amino acids required for biosynthesis between mammalian cells and bacteria, bioorthogonal reactive groups are specifically doped onto the bacterial surface via D-type amino acid derivatives, selectively labeling the bacteria. Through a "point-to-point" reaction between the bacterial surface-active groups and the activated photosensitizer, the photosensitizer is specifically anchored to the bacterial surface and its photodynamic activity is restored, achieving a responsive activation effect in bacteria and improving the precision of treatment.

[0028] Compared to traditional photosensitizers, the photodynamic antibacterial agent provided by this invention has a suitable hydrophilic structure, avoiding the problem of aggregation-induced quenching that may occur during application. Furthermore, due to the preference of mammalian cells for substance uptake, the hydrophilic and negatively charged photodynamic antibacterial agent is not easily taken up by cells, further reducing toxic side effects on normal tissues.

[0029] The activated hydrophilic photodynamic antibacterial agent disclosed in this invention aims to eliminate bacteria at the site of infection without damaging normal tissue. It has good application prospects in bacterial infection-related diseases and also provides new ideas for the design and development of related photosensitizers. Attached Figure Description

[0030] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings, wherein:

[0031] Figure 1 The fluorescence spectra of Tz-BDP-Ar-SO3(A) and Tz-BDP-Ar-2SO3(B) before and after reaction with TOCK in Example 3 are shown.

[0032] Figure 2 The images show the in vitro ROS detection spectra of Tz-BDP-Ar-SO3(A) and Tz-BDP-Ar-2SO3(B) before and after reaction with TOCK in Example 4.

[0033] Figure 3 The results of the cytotoxicity of Tz-BDP-Ar-SO3(A) and Tz-BDP-Ar-2SO3(B) on gastric epithelial cells in the presence or absence of TCOK in Example 5 are presented.

[0034] Figure 4The results of bacterial metabolic labeling of Helicobacter pylori by Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 in Example 6 are shown.

[0035] Figure 5 The in vitro antibacterial results of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 against Helicobacter pylori in Example 7 are shown.

[0036] Figure 6 The results of in vivo antibacterial activity of Tz-BDP-Ar-2SO3 against Helicobacter pylori-infected mice in Example 8 are shown in (A) and (B) in terms of mouse weight monitoring. Detailed Implementation

[0037] The present invention will be further described in detail with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the present invention.

[0038] Example 1: Preparation of compound Tz-BDP-Ar-SO3

[0039]

[0040] Compound 1 was synthesized according to the method disclosed in the reference (Shi W, Li J, He X, Zhou S, Sun H, Wu H. Tuning the Physicochemical Properties of BODIPY for Bioimaging via meso-AminoAcylation. Org Lett. 2022 May 13; 24(18):3368-3372.).

[0041] Synthesis of Compound 2: Compound 1 (0.80 g, 2 mmol) and NIS (1.35 g, 6 mmol) were dissolved in DCM, and one drop of TFA was added. The mixture was stirred at room temperature, and after the reaction was confirmed to be complete by TLC, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc = 2:1) to give compound 2 (0.95 g, 73%) as a deep purple solid. 1 H NMR (400MHz, Chloroform-d) δ8.39(d,J=8.4Hz,2H),7.54(d,J=8.3Hz,2H),6.02(s,2H),2.57(s,6H),1.36(s,6H).

[0042] Synthesis of compound Tz-BDP-Ar-SO3: Compound 2 (98 mg, 0.15 mmol), sodium benzaldehyde-2-sulfonate (125 mg, 0.60 mmol), piperidine (74 μL, 0.75 mmol), glacial acetic acid (43 μL, 0.75 mmol), and molecular sieve ( 200 mg of Tz-BDP-Ar-SO3 was added to 20 mL of anhydrous acetonitrile and reacted under nitrogen protection at room temperature. When the color of the reaction solution changed from purple to green, the reaction solution was filtered, and the molecular sieve was washed with MeOH until a colorless filtrate was obtained. After concentrating the filtrate, it was purified by preparative HPLC to obtain a green solid compound, Tz-BDP-Ar-SO3 (58 mg, 39%). 1 H NMR(400MHz, Methanol-d4)δ9.44(d,J=16.6Hz,2H),8.05(d,J=7.8Hz,2H),7.88(d,J=7.8Hz,2H),7.76-7.66(m,4H), 7.56(t,J=7.6Hz,2H),7.44(t,J=7.6Hz,2H),4.41(t,J=6.0Hz,2H),3.62(t,J=6.1Hz,2H),2.99(s,3H),1.92(s,3H).

[0043] Example 2: Preparation of compound Tz-BDP-Ar-2SO3

[0044]

[0045] Compound 2 (98 mg, 0.15 mmol), sodium benzaldehyde-2,4-disulfonic acid (186 mg, 0.60 mmol), piperidine (74 μL, 0.75 mmol), glacial acetic acid (43 μL, 0.75 mmol), and molecular sieve ( 200 mg of Tz-BDP-Ar-2SO3 was added to 20 mL of anhydrous acetonitrile and reacted under nitrogen protection at room temperature. When the color of the reaction solution changed from purple to green, the reaction solution was filtered, and the molecular sieve was washed with MeOH until a colorless filtrate was obtained. After concentrating the filtrate, it was purified by preparative HPLC to obtain the green solid compound Tz-BDP-Ar-2SO3 (35 mg, 20%). 1 HNMR(400MHz, Methanol-d4)δ9.40(d,J=16.6Hz,2H),8.54(d,J=1.8Hz,2H),8.06-7.87(m,4H), 7.71(d,J=15.7Hz,4H),4.42(t,J=6.1Hz,2H),3.63(t,J=5.1Hz,2H),2.99(s,3H),1.93(s,3H).

[0046] Example 3: Investigation of optical properties of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 before and after reaction with TCOK

[0047] Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 were dissolved in methanol to prepare a stock solution (5 mM). The stock solution was directly diluted in phosphate buffer to a final concentration of 10 μM, and TCOK (50 μM) was added to initiate a bioorthogonal reaction. The mixture was incubated at 37 °C for 2 h, and the optical properties of the solution before and after the addition of TCOK were measured by fluorescence spectroscopy. The results are as follows: Figure 1 As shown, Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 have weak fluorescence due to the fluorescence quenching caused by the combination of photosensitizer and tetrazine. However, after reacting with TCOK, the fluorescence of both is significantly enhanced, indicating that the designed and synthesized photosensitizer has fluorescence activation properties.

[0048] Example 4: In vitro ROS generation efficiency of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 before and after reaction with TCOK

[0049] The changes in singlet oxygen production before and after the reaction of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 with TCOK were assessed using 9,10-anthratridimyl-bis(methylene)dicarboxylic acid (ABDA). Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 were incubated with TCOK in PBS for 2 h, respectively, followed by the addition of ABDA to the mixture. The mixture was then exposed to near-infrared light (665 nm, 50 mW / cm²). 2 Irradiation was performed under [a specific irradiation method], and the absorption peak of ABDA at 400 nm was monitored to evaluate the photodynamic efficiency of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 before and after the reaction with TCOK. The results are as follows: Figure 2 As shown, the binding of tetrazine to the BODIPY core produces a photodynamic quenching effect, significantly reducing ABDA consumption. After reaction with TCOK, the photodynamic activity of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 is restored, and the degradation of ABDA increases significantly after near-infrared irradiation, further demonstrating that the designed and synthesized photosensitizer possesses photodynamic activation properties after a click chemistry reaction. Example 5: Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 Cytotoxicity investigation

[0050] The cytotoxicity of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 to gastric epithelial cells (GES-1 cells) with and without TCOK was detected by the MTT assay. GES-1 cells were inoculated at 1×10⁻⁶ cells / cells. 4GES-1 cells were seeded at a density of cells / well in 96-well plates and incubated overnight at 37°C. The cells were first incubated with TCOK for 12 h, washed twice with PBS, and then different concentrations of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 were added. After 2 h of incubation, the cells were irradiated with near-infrared light (665 nm, 50 mW / cm²) for 10 min. 2 The cells were then incubated for another 24 hours. The unirradiated group was incubated in the dark, and cell viability was assessed. Results are as follows: Figure 3 As shown, Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 are extremely hydrophilic and negatively charged, making them difficult to be taken up through the cell membrane. Therefore, neither of them showed significant cytotoxicity under near-infrared light irradiation, proving that the activating photosensitizer has no toxic side effects on normal tissues.

[0051] Example 6: Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 Bacterial metabolic marker investigation

[0052] Helicobacter pylori ATCC43504 was cultured in BHI liquid medium containing 10% FBS to the logarithmic growth phase and incubated with TCOK (1 mM) for 12 hours. After two washes, Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 were added to the bacterial dispersion and incubated for specific times. For the group without TCOK, the bacteria were directly incubated with Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3. Bacterial surface fluorescence was examined by flow cytometry to evaluate the bacterial-specific labeling effect of the activating photosensitizers. Results are as follows: Figure 4 As shown, without TCOK, neither the Tz-BDP-Ar-SO3 nor the Tz-BDP-Ar-2SO3 groups exhibited significant fluorescence. Conversely, because TCOK containing D-lysine is specifically utilized by bacteria, it modifies the bacterial surface with trans-cyclooctene groups, which can undergo a rapid click chemical reaction with tetrazine groups. Therefore, the fluorescence of the TCOK+Tz-BDP-Ar-SO3 and TCOK+Tz-BDP-Ar-2SO3 groups was significantly enhanced, demonstrating that the activating photosensitizer can specifically label and activate bacteria in situ on the bacterial surface.

[0053] Example 7: Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 In vitro antibacterial effect study

[0054] Helicobacter pylori ATCC43504 was incubated with TCOK for 12 hours. After washing twice, the bacteria were resuspended in BHI (containing 10% FBS) supplemented with Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3. After incubation for 2 hours, the bacteria were examined under near-infrared light (665nm, 50mW / cm²). 2Irradiate for 10 minutes. Dilute the bacteria with PBS and inoculate onto Columbia blood agar plates. The antibacterial activity of Tz-BDP-Ar-SO3 and Tz-BDP-Ar-2SO3 was assessed by the number of colony-forming units (CFU) on the plates. Results are as follows: Figure 5 As shown, the TCOK+Tz-BDP-Ar-SO3 and TCOK+Tz-BDP-Ar-2SO3 groups have extremely strong bactericidal effects, further proving that photosensitizers labeled on bacterial surfaces can generate ROS under light irradiation, thereby achieving the purpose of specific bactericidal action.

[0055] Example 8: Investigation of the antibacterial effect of Tz-BDP-Ar-2SO3 in a mouse model infected with Helicobacter pylori

[0056] To establish a mouse model of Helicobacter pylori infection, C57BL / 6 mice were treated daily with a Helicobacter pylori solution (1.5 × 10^6 mg / L). 7 CFU / mouse was administered via gavage for one week. Two weeks after infection, three infected mice were randomly sacrificed, and the infection status was detected by urease test. Subsequently, C57BL / 6 mice infected with Helicobacter pylori were randomly divided into four groups (n=5) and treated differently: 1) Saline (+), administered via gavage for 3 consecutive days; 2) TCOK + Tz-BDP-Ar-2SO3 (-), TCOK was administered via gavage 3 times / day for 2 days, and Tz-BDP-Ar-2SO3 was administered via gavage on the 3rd day; 3) Tz-BDP-Ar-2SO3 (+), Tz-BDP-Ar-2SO3 was administered via gavage only on the 3rd day; 4) TCOK + Tz-BDP-Ar-2SO3 (+), TCOK was administered via gavage 3 times / day for 2 days, and Tz-BDP-Ar-2SO3 was administered via gavage on the 3rd day. The dosages of TCOK and Tz-BDP-Ar-2SO3 were 30 mg / kg and 5 mg / kg, respectively. Body weight was recorded daily. Two hours after administration on day 3, the saline (+), Tz-BDP-Ar-2SO3 (+), and TCOK+Tz-BDP-Ar-2SO3 (+) groups were treated with a 665nm laser (0.4W / cm²) via a transesophageal fiber-coupled laser system. 2 The stomachs of mice were irradiated for 5 minutes. Twenty-four hours after treatment, the mice were sacrificed, and stomach tissue was collected to measure antibacterial activity. Results were as follows: Figure 6As shown, the bactericidal effect of the Tz-BDP-Ar-2SO3(+) group was relatively weak. Conversely, the bacterial survival rate of the TCOK+Tz-BDP-Ar-2SO3(+) group irradiated with near-infrared light was significantly reduced. This is because the photosensitizer specifically binds to the bacterial surface and effectively removes the photodynamic shielding group, achieving in-situ activation of the photosensitizer on the bacterial surface and shortening the interaction distance between the photosensitizer and bacteria. This results in the generation of a large amount of ROS under near-infrared light irradiation, effectively clearing bacteria from the infected site. Furthermore, the mice did not experience significant weight changes during treatment, indicating that this treatment modality has good safety.

Claims

1. An activated water-soluble photodynamic antibacterial agent based on bacterial bio-orthogonal labeling, characterized in that, A BODIPY-based compound of Formula I: Formula I wherein R1is a tetrazine click chemistry reactive group with fluorescence and photodynamic quenching effect: ; R2 is a halogen atom Cl, Br or I; R3 is a hydrophilic modifying group: , , , , , , , , .

2. The water-soluble activated photodynamic antibacterial agent based on bacterial bio-orthogonal labeling according to claim 1, characterized in that, R1in formula I is a group selected from: ; R2 is a halogen atom Cl, Br or I; R3 is the following group: , , , , , .

3. The water-soluble activated photodynamic antibacterial agent based on bacterial bio-orthogonal labeling according to any one of claims 1-2, characterized in that, The photoactive antibacterial agent has the following structure: 、 、 、 、 、 。 4. The water-soluble activated photodynamic antibacterial agent based on bacterial bio-orthogonal labeling according to any one of claims 1-2, characterized in that, The heavy atom effect of halogen promotes the intersystem crossing of photosensitizer and improves the efficiency of singlet oxygen generation, wherein the introduction of iodine atom has the highest singlet oxygen generation efficiency.

5. The water-soluble activated photodynamic antibacterial agent based on bacterial bio-orthogonal labeling according to any one of claims 1-2, characterized in that, The absorption wavelength of the activated water-soluble photoactive antibacterial agent is 600-650 nm.

6. The water-soluble activated photodynamic antibacterial agent based on bacterial bio-orthogonal labeling according to any one of claims 1-2, characterized in that, The emission wavelength of the activated water-soluble photoactive antibacterial agent is 650-700 nm.

7. The water-soluble activated photodynamic antibacterial agent based on bacterial bio-orthogonal labeling according to any one of claims 1-2, characterized in that, The activated water-soluble photoactive antibacterial agent can avoid being taken up by normal cells, thereby reducing the phototoxicity to normal tissues.

8. The water-soluble activated photodynamic antibacterial agent based on bacterial bio-orthogonal labeling according to any one of claims 1-2, characterized in that, The activated water-soluble photoactive antibacterial agent is modified with a tetrazine click chemistry reaction group, which can quench the fluorescence and ROS generation capacity of the photosensitizer, but when it reaches the site of bacterial infection, it can reverse this quenching effect by undergoing a rapid click chemistry reaction with the active group trans-cyclooctene-D-lysine inserted on the bacterial peptidoglycan, thereby achieving specific labeling and activation of the photosensitizer on the bacterial surface.

9. The water-soluble activated photodynamic antibacterial agent based on bacterial bio-orthogonal labeling according to any one of claims 1-2, characterized in that, After specific labeling and activation on the bacterial surface, the activated water-soluble photoactive antibacterial agent can selectively kill bacteria under the irradiation of near-infrared light without damaging normal tissues.

10. The method of claim 1-2 for the synthesis of an activated water-soluble photodynamic antibacterial agent based on bacterial bio-orthogonal labeling, characterized in that, The synthesis steps are as follows: first, synthesize a BODIPY mother nucleus with an R1 group; then introduce a halogen atom-substituted moiety at the 2,6 positions of the mother nucleus; finally, modify the 3,5 positions of the mother nucleus with a hydrophilic aromatic aldehyde through Knoevenagel condensation reaction, thereby obtaining the activated hydrophilic photoactive antibacterial agent.

11. Use of a bacterial bio-orthogonal label-based activated water-soluble photodynamic antibacterial agent according to any one of claims 1-2 for the preparation of a medicament for the treatment of bacterial infections, characterized in that, The bacterial infection is selected from oral bacterial infection, wound bacterial infection and Helicobacter pylori infection.

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