Sang Shen Pu Gong Ying beverages can significantly inhibit multi-drug resistant organisms-multiple dimensions of evidences

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Sang Shen Pu Gong Ying beverages can significantly inhibit multi-drug resistant organisms-multiple dimensions of evidences

https://doi.org/10.21203/rs.3.rs-4956501/v1

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Background The surge in multi-drug resistant organisms (MDROs) poses a dire threat to global health, necessitating novel antibacterial strategies. Traditional Chinese medicine (TCM) offers a multi-level approach potentially mitigating resistance development.

Methods We evaluated the Sang Shen Pu Gong Ying (SSPGY) beverage’s antibacterial activity through in-vitro tests, real sputum samples, and a clinical case study. The beverage, rooted in TCM, was prepared using a blend of medicinal and food homologous herbs and tested for its effect on MDROs, including minimal inhibitory concentration (MIC) determination.

Results In-vitro bacteriostatic assays indicate that SSPGY beverage can significantly reduce MDROs, including Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii, and penicillin-resistant Streptococcus pneumoniae with distinct antibacterial effects from conventional antibiotics. However, it showed ineffective inhibitory activity in sputum samples. Amazingly, by a intermittent 165-d intervention of SSPGY beverage to a clinical case of severe Klebsiella pneumoniaeinfection, it manifests the effectiveness against MDROs and play an essential role in combating antibiotic resistance.

Conclusion Our findings indicate that SSPGY, with its unique antibacterial profile, could offer a promising alternative or intervention to traditional antibiotics. Further research is warranted to elucidate its mechanisms and optimize its therapeutic potential in the context of MDROs.

Infectious Diseases

multi-drug resistant organism (MDRO)

Sang Shen Pu Gong Ying (SSPGY) beverage

Medicinal and food homologous

Nosocomial infections

Traditional Chinese medicine (TCM)

In contemporary society, the emergence of antimicrobial resistance has escalated into a pressing global public health concern, ¹ with the proliferation of multi-drug resistant organism (MDRO) presenting a formidable challenge to the management and treatment of clinical infectious diseases. The escalating complexity in treating infections, and in some cases, their untreatability, is a direct consequence of the diminished efficacy of antibiotics due to their overuse. ² The emergence and dissemination of MDRO are predominantly can be attributed to the egregious misuse of antimicrobial agents, culminating in severe repercussions inclusive of organ dysfunction and septicemia. To date, no antibiotic has been identified that can definitively address the issue of resistant strains and the demise of antibiotics discovery brings the spectre of incurable infections. ³ It’s anticipated that the emergence of antibiotic resistance will persist, potentially even in the face of the most robust research and development efforts aimed at crafting novel pharmaceuticals. Left unaddressed, the issue of drug resistance may culminate in a scenario characterized by a lack of effective pharmaceutical interventions. Concurrently, the escalating severity of bacterial resistance is exacerbated by widespread misuse of antibiotics in both medical and agricultural settings, as highlighted by WHO as a significant threat. ⁴

On May 17th, 2024, WHO issued the Bacterial Priority Pathogens List (BPPL) 2024, which updates and refines the prioritization of antibiotic-resistant bacterial pathogens to address the evolving challenges of antibiotic resistance (https://www.who.int/publications/i/item/9789240093461) with the purpose to highlight the significant global implications of infectious diseases, encompassing the burden they impose, as well as key aspects such as transmissibility, therapeutic manageability, and available preventative measures. Furthermore, the list serves to delineate the research and development trajectory for novel treatments and to track the evolution of resistance patterns. In this paper, we also used some of the bacteria in the list to ensure that the representation of the work.

Antibiotics have traditionally been the cornerstone of treating bacterial infections. However, their efficacy is waning against multi-drug resistant organisms (MDROs), with the emergence of “superbugs” further complicating the situation. The quest for new antibiotics has hit a bottleneck, evidenced by a dearth of recent discoveries. ⁵ Although theoretical frameworks, such as Wong’s ⁶ substructure-based approach leveraging deep learning for the discovery of new antibiotic classes, are promising, their transition to clinical application has yet to be realized. In response to these hurdles, the scientific community has shifted its focus towards innovative solutions to combat antimicrobial resistance. With a particular focus on identifying viable alternative solutions, such as the use of bacteriophages, ⁷ natural viruses that target and destroy specific bacteria, offering a highly specific and less resistance-prone approach. Additionally, immunotherapies, ⁸ a field that leverages the body's immune system to combat infections, is currently at the forefront of medical research which is redefining our understanding of how to harness the innate defenses of the body against pathogens. Concurrently, the modulation of the microbiome, ^{9, 10} as the intricate community of microorganisms within our bodies, is another area of research that could influence microbial balance for therapeutic purposes. These alternative strategies are not only considered as complementary to conventional antibiotics but also acting as potential replacements. ¹¹

In the pursuit of innovative antibacterial approaches, traditional Chinese medicine (TCM) has emerged as a noteworthy contender ¹². Rooted in a deep historical context and a legacy of efficacy in treating infectious diseases, TCM operates on a multi-target antibacterial mechanism that diverges from the single-target approach of conventional antibiotics. This mechanism is characterized by a multifaceted intervention at various biological levels, potentially reducing the likelihood of resistance development. TCM’s extensive pharmacopeia of natural compounds has been a cornerstone of traditional healing for centuries, which are readily accessible and have been utilized for centuries in traditional healing practices. The diversity of natural bioactive ingredients of TCM not only provides a wide-ranging therapeutic spectrum but also suggests a reduced propensity to induce drug resistance. ^{12, 13}

The philosophy of TCM embraces the concept of “Medicinal and Edible”, which underscores the therapeutic potential of food-derived substances. ¹⁴ This approach is rooted in the belief that such substances can not only nourish the body but also provide healing benefits without adverse effects, a principle referred to as “Piansheng”. In this context, Sang Shen Pu Gong Ying (SSPGY) beverage, produced by Hong Kong TungTakSim Biotechnology Co., Ltd., exemplifies the application of TCM principles in a modern dietary supplement. Official documents have granted approval for its sale in China and Russia, marking a significant milestone in the integration of TCM-derived products into the global healthcare market. Recent studies have indicated that SSPGY significantly inhibits the growth of multi-drug resistant bacteria as a nutritional supplement positioning it a potential ally in the fight against antibiotic resistance. The beverage’s therapeutic claims were supported by evidences, including reports of its efficacy in treating COVID-19 cases (as shown in Figure S1).

In this work, we introduced a safe and reliable medicinal and food homologous beverage-SSPGY to testify the significant anti-bacteria activity in multiple dimensions of evidences, including in-vitro antibacterial test, antibacterial test of real sputum samples and a patient with severe Klebsiella pneumoniae infection which is obviously distinct from the traditional antibiotics therapy. These findings are of great significance for the discovery and exploration of antibacterial effects and antimicrobial properties. It represents an emerging and promising alternative in antibiotic resistance treatment.

2.1 Bacterial strains

The cultured and tested strains and sputum samples were derived from the Center of Clinical Laboratory and Pathology, South China Hospital of Shenzhen University which including the quality control strains in routine bacteriological laboratory and the bacteria in WHO BPPL belonging to critical, high and medium group which were isolated from the samples of patients and stored at -80 ℃. The strains selected in this experiment were listed in Table S1.

2.2 Preparation of SSPGY beverage

SSPGY beverage has launched in 2008 and marketed for over 16 years and has been recognized as a legal and safe food product. The ingredients are composed of more than 30 varieties of medicinal plants and ingredients which classified as TCM and food homologous herbs, such as mulberry, dandelion, ginger, honey, peach, yellow essence, mint, lotus seed, and other components. The registration number in China is CHKG24072301100004 and certified by the Center for Food Safety, Food and Environmental Hygiene Department of Hong Kong with the certificate number FIC-23-0003 (Figure S2). The production process of these beverages adheres to traditional techniques, including fermentation and decocting, which are the cornerstones of TCM. Type A, B and C of the beverages were employed to test the effectiveness which share a primary ingredient; and the manufacturing processes is slightly different. For proprietary reasons, the specific formulation and manufacturing methods of SSPGY beverage cannot be disclosed. The package of the beverage is 300 mL per bottle, providing a convenient and standardized serving size.

2.3 Bacteriostasis experiment by the filter paper method

The filter paper was uniformly cut into 10×10 mm squares and arranged symmetrically around the periphery of a bacteriological culture dish containing solid agar medium. This setup allowed for precise application of the test liquid to the filter paper squares. Each square received 10 µL beverage, which was allowed to absorb completely and evaporate, ensuring consistent exposure conditions. Sterile saline served as a control to account for any non-specific effects. This meticulous application process was conducted in triplicate to ensure the reliability of our results. Following the application, the culture dishes were sealed to maintain a controlled environment and incubated at a constant temperature of 37 ℃ for 24 h. This incubation period was chosen to promote bacterial growth and allow for the assessment of the beverage's antibacterial activity.

2.4 Dilution method by solid agar plate

The bacteriostatic qualitative test of the filtered fluid of SSPGY beverage were determined and assessed by solid agar plate bacteriostatic assay. The minimal inhibitory concentration (MIC) of the filtrate was ascertained through a serial dilution methodology. Each experimental group was replicated thrice to ensure statistical rigor, with an additional negative control group that exclusively contained sterilized saline for comparative analysis.

2.5 Bacteriostatic test on sputum of patients in real world

A total of 48 clinical sputum samples were were collected, cultured and tested by Clinical Laboratory of South China Hospital were listed in Table S1. The results of routine microbial culture identification showed that the specimens collected included normal respiratory tract flora specimens and MDROs including gram-positive pathogenic bacteria (Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, etc.), and gram-negative pathogenic bacteria [Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli (E. coli), etc.].

Initially, each sample was subjected to a standardized preparation process: three bottles of sample A, B and C were put in 100 ℃ water bath in 10 min before mixing with the sputum specimen. 1 mL Sample A was pipetting and mixing with 1 mL of sputum specimen carefully to avoid contamination by 1:1, 1:2 and 1:4 (v/v) for 30 s by shaking and mixing and inverting and gently shaking for 40 min at 35 ℃ incubation, respectively. After that, 50 µL of mixtures by different mixing ratios were inoculated with blood agar plate and perform routine three-zone streak inoculation for 24 h, respectively. The control three sub-groups were treated with normal saline (NS) in 1:1, 1:2 and 1:4 (v/v) with sputum specimen. The same processes were used in Type B and C of SSPGY beverage.

2.6. Intervention by SSPGY beverage for a patient with severe Klebsiella pneumoniae infection

The study has been approved by the Ethics Committee of South China Hospital of Shenzhen University (No. HNLS20221209001-A). In Dec. 13, 2023 (as the 1st day in hospital), a Chinese female with the age of 54-year-old was admitted to Shangqiu Central Hospital in Henan Province as the following diagnoses: (1) Coma; (2) Type II respiratory failure; (3) Acute coronary syndrome; (4) Amyotrophic lateral sclerosis (ALS); (5) Respiratory acidosis; (6) Hyperlactacidemia; (7) Pneumonia respiratory acidosis. She presented with unexplained fever and respiratory symptoms, including shortness of breath, and wheezing, with a body temperature of approximately 38 ℃. Initial sputum culture on Dec. 26, 2023, during her first hospitalization, identified a Klebsiella pneumoniae infection. Despite antibiotic therapy administered across four different medical facilities and intermittent supportive care due to her physical frailty, the patient’s condition did not significantly improve during her stays from Dec. 12, 2023, to Mar. 19, 2024 because of her physical weakness and treatment in local intensive care unit (ICU). The patient’s treatment regimen included the intermittent use of SSPGY beverage, which she consumed from the time of hospital discharge until Jun. 4, 2024. Throughout her hospitalization and post-discharge period, the administration of this beverage and the outcomes of subsequent bacterial cultures are detailed in Figure S3. The patient’s case highlights the challenges in managing severe infections and underscores the need for effective treatment strategies, particularly in immuno-compromised individuals.

3.1 In-vitro bacteriostatic assays

Antimicrobial properties of Type A SSPGY beverage were evaluated against a panel of common respiratory pathogens that are prevalent in clinical pulmonary infections, including Streptococcus pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter baumannii, Staphylococcus aureus and Streptococcus pyogenes. Our findings indicate that this beverage significantly reduces the viability of these organisms, particularly those resistant to first-line treatments such as Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii, as well as penicillin-resistant Streptococcus pneumoniae. The effectiveness of the beverage increased with the concentration of the extract in the test mixture. However, we did not observe any inhibitory effect on Klebsiella pneumoniae, E. coli and Enterococcus faecium, suggesting a selective antimicrobial action (Figure. 1).

Figure 1

Type B of the beverage, like its predecessor, displayed a discernible inhibitory impact on a spectrum of multi-drug resistant bacteria, including Streptococcus pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter baumannii, Staphylococcus aureus and Streptococcus pyogenes. Notably, the beverage was effective against particularly challenging clinical strains, such as carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Acinetobacter baumannii and penicillin-resistant Streptococcus pneumoniae. The observed dose-response relationship paralleled that of Type A, reinforcing the consistent nature of the beverage's antimicrobial potency. Nevertheless, no significant inhibitory activity was detected against Klebsiella pneumoniae, E. coli, Enterococcus faecium and Proteus mirabilis (Figure. S4).

We have determined identified that both Type A and B filtrates derived from SSPGY beverage possessed significant antibacterial activity against Stenotrophomonas maltophilia, with MIC of 0.5. This concentration also demonstrated a substantial anti-hemolytic effect on Streptococcus pyogenes. Furthermore, MIC for additional MDR bacterial strains-namely Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus-was uniformly found to be 1. These MICs were ascertained through a dilution method, and the outcomes are presented graphically in Figure. 2.

Figure 2

3.2 Bacteriostatic test on sputum of patients in real world

Following a 24 h-incubation at 35°C on blood agar plates, the control group (Figure. 3A1-A3, B1-B3 and C1-C3) displayed robust bacterial growth across all three distinct zones, with well-defined colonies characteristic of the normal respiratory. In comparison, the cultures treated with different dilution ratios of Type A, B, and C exhibited a range of inhibitory effects. These effects were observed in the form of altered colony morphology, reduced species diversity, and decreased quantity and vigor of growth compared to the control (Figure. 3A4-A6, B4-B6, and C4-C6). Notably, an increase in the volume ratio of the beverage mixture corresponded to a more pronounced inhibitory effect on the bacterial strains tested.

Figure 3

Upon examination of the blood agar plates, the colonies were characterized by their yellow color, large size, and circular, smooth, convex, and moist appearance, each encircled by a complete translucent zone of hemolysis-a typical feature of Gram-positive bacteria (Figure. 4A1-A3, B1-B3, and C1-C3). A pathogenic Staphylococcus aureus, specifically methicillin-resistant Staphylococcus aureus (MRSA) was identified in the sputum specimen in these blood agar plates. As one of the important and common MDROs, the clinical manifestations of MRSA infection include asymptomatic nasal colonization, mild skin and soft tissue infections, and aggressive outbreaks with high mortality ¹⁵. However, when comparing the colonies grown in the presence of varying concentrations of the Type A, B, and C mixtures of the SSPGY beverage to the control groups, no significant differences were observed in the morphological characteristics, color, or growth conditions of the colonies (Figure. 5A4-A6, B4-B6, and C4-C6). The reason might attribute to the thick cell wall on the surface of MRSA, and the encapsulation of the sputum, thereby limiting its efficacy in inhibiting MRSA growth. This is different from the killing of MRSA in standard solution, suggesting that the environment and state of the beverage significantly influence its bactericidal properties.

Figure 4

Figure 5

In the blood agar plates, mixed cultures of Gram-negative stain could be observed, where the inhibitory effects of Type A, B, and C mixtures of SSPGY beverage were notably increased as the mixing ratios varied from 1:1 to 1:3 (Figure. 5A4-A6, B4-B6 and C4-C6) compared to the control groups (Figure. 5A1-A3, B1-B3 and C1-C3). Our findings suggest that the components Type A, B, and C of SSPGY beverage have a significant inhibitory effect on Gram-negative pathogens present in sputum specimens.

3.3 The intervention by SSPGY beverage

The results of bacterial culture in the whole administration and follow-up of the patient during the intervention of SSPGY beverage in Dec. 12, 2023 to Jun. 4th, 2024 was exhibited in Figure S3. In terms of the interventions by SSPGY beverage, the situation of drug resistance in patients showed a downward trend. In ICU patients, some pathogens such as Pseudomonas aeruginosa, ¹⁶ Klebsiella pneumoniae, ¹⁷ and E. coli show resistance to a variety of commonly used antibiotics, which poses a challenge to clinical treatment and requires further investigates.

It demonstrated the species and survival times of the related MDROs encountered in this case (Fig. 6A). The complexity of treating infections with the conventional antibiotics has been surpassed, as these treatments no longer effectively control or inhibit the growth of MDROs. Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and E. coli could be found in Liu’s sputum and urine samples (Fig. 6A). E. coli acts as one kind of common and typically antibiotic-sensitive strain, is the most susceptible strain to be killed with a 2 d-survival rate. In contrast, the more persistent MDROs, despite intervention with the SSPGY beverage, survived for 140, 69, and 46 d, respectively (Fig. 6A).

Throughout the treatment period, procalcitonin (PCT) levels remained within the normal range, and C-reactive protein (CRP) levels kept normal after the 39 d of therapy as depicted in Figure. 5B. The three indexes of infectious diseases such as white blood cell (WBC), neutrophil (NEUT) and lymphocyte (LYM) were all abnormal at the time of admission, and gradually returned to normal by day 33 from the 33rd d, except for the 83rd and 120th d, most of the measured values were within the normal range during this period (Figure. 5C). The spike on the 83rd d, Mar. 6, coincided with the cessation of the beverage intake; while the increase on the 120th d, Apr. 15, occurred three days post-hospital discharge.

Figure 6

Infections caused by MDROs frequently present with complex clinical challenges that require advanced antimicrobial therapies. The infections can exacerbate patient distress, prolong hospital stays, increase healthcare expenditures, and in severe instances, result in fatal outcomes. And as an excellent representative of TCM practices, SSPGY beverage can be considered as a milestone of TCM nutrition for it’s the first time to reports this innovative scientific discovery of its “drug homologous food” property in suppressing MDROs and the application to control the infection in patients with multiple dimensions of evidences.

TCMs such as Dian Dao San, ¹⁸ berberine, ¹⁹ Bletilla striata polysaccharide, ²⁰ and madecassic acid ²¹ were used for anti-bacteria and the effectiveness was confirmed by in-vitro experiments. Clinic trials reported maxingshigan-weijing decoction is more effective in the management of COVID-19 patients compared to those treated with routine supportive care alone. ²² The prevention of nosocomial infection in elderly population (A total of 110 elderly patients) by Gubiao Pixie prescription was reported and has a role in enhancing immune function and antibacterial and bactericidal effect. ²³ The preventive effect on nosocomial infection in these susceptible people are evident. Compared with the above-mentioned works, we have released multiple dimensions of evidences of SSPGY beverage’s antibacterial profile, including in-vitro tests, real sputum samples, and a clinical case study, which provides a more nuanced understanding of the beverage’s potential as an adjunct or alternative to conventional antibiotics. As an innovative approach to nutritional therapy for pathogen inhibition, preliminary clinical observations suggest that the beverage is both effective and safe, lacking adverse side effects and even showing potential to repair damaged immune system.

If in the future, this treatment proves viable for widespread use in managing and controlling MDRO infections, it could potentially reduce the necessity for various antibiotics with resistance concerns. This shift could lead to a decrease in clinical MDR prevalence, effectively lowering infection rates and mortality associated with resistant strains. Such a development would offer a promising perspective for patients affected by MDRO infections.

The clinical intervention by SSPGY beverage for the case with severe Klebsiella pneumoniae infection highlights its value and significance. In the early stages, the effect of SSPGY does not seem to show evident effect. The 33rd d could be marked as a pivotal moment in the patient’s illness progression. Prior to this date, numerous clinical indicators deviated from the normal range, indicating the presence of resistant bacteria. The introduction and subsequent cessation of intervention with SSPGY beverage corresponded with periods of bacterial inhibition and resurgence, respectively. These observations suggest that the beverage is effective against MDROs which might due to their enhancement of the susceptibility of MDROs, potentially reduce the dosage of antibiotic and the rate of drug resistance. ¹² From another perspective, the patient’s immune system was actively engaged in a continuous process of renewal and repair during the administration of the beverage, facilitating the clearance of pathogens from the body.

Consequently, a comprehensive understanding of the pathogenic microorganisms present in a patient’s sputum is essential for guiding clinical decision-making. It’s critical for the accurate diagnosis, selection of appropriate antimicrobial therapies, and the development of effective infection control strategies. ^{1, 24}

Our work uncovers SSPGY beverage possesses a bactericidal effect against MDROs and exhibits growth-inhibitory properties against persistent MDRO clinical isolates. This indicates a novel antibacterial mechanism distinct from traditional antibiotics. The implications of this study are profound, potentially reshaping the landscape of global medicine with an impact reminiscent of the discovery of penicillin in 1928. ²⁵ This work introduces a safe and reliable “Chinese solution” to the global urgent challenge of MDRO, representing a significant contribution to TCM. Our findings are not only broadening the horizons of medical science but also opening new frontiers in the fight against infectious diseases and the management of bacterial resistance. Looking ahead, we are committed to delving deeper into the antibacterial mechanism of SSPGY beverage against MDROs. Future research will encompass a multi-faceted approach, including molecular, cellular, animal studies, and clinical trials, to fully unravel the potential of TCM in combating MDR bacteria.

Contributors

ALL, Chihang M, and NL conceived the study and wrote the study protocol. MW, XL, CC, and DC, implemented the field activities. Chihim M and Chihang M trained and monitored the staff on data collection and management. SL trained the staff on sample collection, storage, and transport and performed the bacteriostasis experiment in Center of Clinical Laboratory and Pathology. ZL, TL, QJ, XS, and GF accessed and verified the underlying data in the manuscript. NL wrote the first draft of the paper. All authors had full access to the data in the study and had final responsibility for the decision to submit for publication.

Declaration of interests

Chihim Mak and Chihang Mak are the senior executives of Hong Kong TungTakSim Biotechnology Co., Ltd., Hong Kong, and supported this research, they received no personal financial payment for this work. All other authors declare no competing interests.

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Data sharing

De-identified participant epidemiological, clinical, and laboratory data, the study statistical analysis plan, and informed consent forms can be made available according to the Shenzhen University, and Guangzhou University of Chinese Medicine data sharing policy on request to the corresponding author (NL), starting from the time of publication and for the subsequent 3 years.

Acknowledgments

We thank the study participants, and our local collaborators and field staff. We received funding from the National High Technology Research and Development Program of China (Nos. 2015AA020940 and 2013AA020418) and the National Natural Science Foundation of China (No.81872584).

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Table S1 is not available with this version

The authors declare potential competing interests as follows: Chihim Mak and Chihang Mak are the senior executives of Hong Kong TungTakSim Biotechnology Co., Ltd., Hong Kong, and supported this research, they received no personal financial payment for this work. All other authors declare no competing interests.

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Sang Shen Pu Gong Ying beverages can significantly inhibit multi-drug resistant organisms-multiple dimensions of evidences

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Abstract

Figures

1. Introduction

2. Materials and methods

2.1 Bacterial strains

2.2 Preparation of SSPGY beverage

2.3 Bacteriostasis experiment by the filter paper method

2.4 Dilution method by solid agar plate

2.5 Bacteriostatic test on sputum of patients in real world

2.6. Intervention by SSPGY beverage for a patient with severe Klebsiella pneumoniae infection

3. Results

3.1 In-vitro bacteriostatic assays

3.2 Bacteriostatic test on sputum of patients in real world

3.3 The intervention by SSPGY beverage

4. Discussion

5. Conclusion

Declarations

References

Table

Additional Declarations

Supplementary Files

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