Contribution of Streptococcus pseudopneumoniae and Streptococcus salivarius to vocal fold mucosal integrity and function.

Structural changes to the vocal fold (VF) epithelium, namely, loosened intercellular junctions, have been reported in VF benign lesions. The potential mechanisms responsible for the disruption of cell junctions do not address the contribution of resident microbial communities to this pathological phenomenon. In this study, we focused on determining the relationship between Streptococcus pseudopneumoniae (SP), a dominant bacterial species associated with benign lesions, and Streptococcus salivarius (SS), a commensal bacterium, with human VF epithelial cells in our three-dimensional model of the human VF mucosa. This experimental system enabled direct deposition of bacteria onto constructs at the air/liquid interface, allowing for the assessment of bacterium-host interactions at the cellular, molecular and ultrastructural levels. Our findings demonstrate that SP disrupts VF epithelial integrity and initiates inflammation via the exported products HtrA1 and pneumolysin. In contrast, SS attaches to the VF epithelium, reduces inflammation and induces Mmp2-mediated apical desquamation of infected cells to mitigate the impact of pathogens. In conclusion, this study highlights the complexity of microbial involvement in VF pathology and potential VF mucosal restoration in the presence of laryngeal commensals.

Streptococcus salivarius K12 Alleviates Oral Mucositis in Patients Undergoing Radiotherapy for Malignant Head and Neck Tumors: A Randomized Controlled Trial.

PURPOSE: Oral mucositis (OM) is a common debilitating toxicity associated with radiotherapy (RT) for malignant head and neck tumors. This prospective, randomized, double-blind, placebo-controlled trial aimed to evaluate the efficacy and safety of Streptococcus salivarius K12 (SsK12) in reducing the incidence, duration, and severity of severe OM (SOM). METHODS: A total of 160 patients with malignant head and neck tumors undergoing definitive or postoperative adjuvant RT were randomly assigned (1:1) to receive SsK12 probiotic (n = 80) or placebo (n = 80) at West China Hospital, Sichuan University, Chengdu, China. Patients were instructed to suck SsK12 or placebo lozenges thrice daily from the initiation to the end of RT. OM was evaluated twice a week during RT and once a week thereafter for up to 8 weeks. The primary end point was the incidence of SOM. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. RESULTS: Baseline patient characteristics were similar in the SsK12 and placebo groups. The incidence of SOM was significantly lower in the SsK12 group as compared with the placebo group (36.6% v 54.2%; P = .0351). The duration (median, 0.0 days v 7.0 days; mean, 8.9 days v 18.3 days; P = .0084) and time to develop SOM (median, not estimable v 42.0 days; hazard ratio, 0.55 [95% CI, 0.34 to 0.89]; log-rank test: P = .0123) were also improved in the case of the SsK12 group. Adverse events were similar between the groups, and mild or moderate gastrointestinal reactions (flatulence or dyspepsia) associated with the lozenges were observed in two patients in the SsK12 group. High-throughput sequencing results indicated that SsK12 inhibited opportunistic pathogens and enriched oral commensals during RT. CONCLUSION: In this prospective, randomized clinical trial, SsK12 probiotic significantly reduced the incidence, onset, and duration of SOM with a good safety profile.

Noniatrogenic Meningitis Caused by Streptococcus salivarius Associated with Early Esophageal Cancer and Early Gastric Cancer.

Streptococcus salivarius is part of the normal oral cavity and gastrointestinal tract microflora and an unusual cause of acute bacterial meningitis. We herein report an 81-year-old man with S. salivarius meningitis, which led to a diagnosis of early esophageal cancer and early gastric cancer. S. salivarius infection may occur through the gastrointestinal mucosa when it is disrupted in association with early gastrointestinal cancer. To our knowledge, this is the first report describing S. salivarius meningitis associated with multiple early gastrointestinal cancers in the absence of other sources of infection.

Streptococcus lactarius MB622 and Streptococcus salivarius MB620 isolated from human milk reduce chemokine IL-8 production in response to TNF-α in Caco-2 cell line, an exploratory study.

Streptococci are a predominant genera of the human milk microbiome. Among different lactic acid bacteria (LAB) a few Streptococcal strains are also considered as probiotics. Probiotic bacteria are reported to modulate immunity when consumed in adequate amount and bacterial hydrophobicity can be considered as a preliminary experiment for the adhesive capability of probiotic bacteria to the epithelial cells. The present study aimed to investigate the probiotic, hydrophobic and immune modulation property of Streptococcus lactarius MB622 and Streptococcus salivarius MB620, isolated from human milk. S. lactarius MB622 and S. salivarius MB620 displayed higher hydrophobicity (78 % and 59 % respectively) in addition to intrinsic probiotic properties such as gram positive classification, catalase negative activity, resistance to artificially stimulated gastric juice and gastrointestinal bile salt concentration. In conclusion Streptococcus lactarius MB622 and Streptococcus salivarius MB620 isolated from human milk when administered in sufficient amount and for certain duration could be used to reduce inflammation inside the colon by reducing the production of inflammatory booster (IL-8) in diseased state.

Lyophilized cell-free supernatants of the oral probiotics Streptococcus salivarius M18 and Streptococcus salivarius K12 show promises for milk safety.

The functional food ingredients market has been growing due to the preferences for healthier, nutritional, environment-friendly, and convenience foods. Here, we evaluated the antimicrobial potential of the lyophilized cell-free supernatants of the two most promising oral probiotic strains Streptococcus salivarius M18 and S. salivarius K12 on Pseudomonas aeruginosa to be applied for safety purposes in the milk. We showed that the lyophilized culture supernatant of the strain M18 inhibited the pathogen growth in milk by about 75%, 70%, and 60% when incubated at 37°C, room temperature, and +4°C, respectively. The inhibition levels were about 50%, 30%, and 45% for the lyophilized K12 cell-free supernatant. Besides, the lyophilized culture supernatants of the oral probiotics, especially of S. salivarius M18, exhibited anti-cancer activities on colon cancer cells in vitro. Thus, the results of this manuscript suggest that the cell-free supernatants of the M18 and K12 strains are potential candidates, which merit more investigation for their applications, as biopreservatives in foods and beverages and as anti-cancer biotics for human health.

Effect of a bacteriocin-producing Streptococcus salivarius on the pathogen Fusobacterium nucleatum in a model of the human distal colon.

The gut microbiome is a vast reservoir of microbes, some of which produce antimicrobial peptides called bacteriocins that may inhibit specific bacteria associated with disease. Fusobacterium nucleatum is an emerging human bacterial pathogen associated with gastrointestinal diseases including colorectal cancer (CRC). In this study, fecal samples of healthy donors were screened for potential bacteriocin-producing probiotics with antimicrobial activity against F. nucleatum. A novel isolate, designated as Streptococcus salivarius DPC6993 demonstrated a narrow-spectrum of antimicrobial activity against F. nucleatum in vitro. In silico analysis of the S. salivarius DPC6993 genome revealed the presence of genes involved in the production of the bacteriocins salivaricin A5 and salivaricin B. After 6 h in a colon fermentation model, there was a significant drop in the number of F. nucleatum in samples that had been simultaneously inoculated with S. salivarius DPC6993 + F. nucleatum DSM15643 compared to those inoculated with F. nucleatum DSM15643 alone (mean ± SD: 9243.3 ± 3408.4 vs 29688.9 ± 4993.9 copies/µl). Furthermore, 16S rRNA amplicon analysis revealed a significant difference in the mean relative abundances of Fusobacterium between samples inoculated with both S. salivarius DPC6993 and F. nucleatum DSM15643 (0.05%) and F. nucleatum DSM15643 only (0.32%). Diversity analysis indicated minimal impact exerted by S. salivarius DPC6993 on the surrounding microbiota. Overall, this study highlights the ability of a natural gut bacterium to target a bacterial pathogen associated with CRC. The specific targeting of CRC-associated pathogens by biotherapeutics may ultimately reduce the risk of CRC development and positively impact CRC outcomes.

Gastric Non-Helicobacter pylori Urease-Positive Staphylococcus epidermidis and Streptococcus salivarius Isolated from Humans Have Contrasting Effects on H. pylori-Associated Gastric Pathology and Host Immune Responses in a Murine Model of Gastric Cancer.

In populations with similar prevalence of Helicobacter pylori infection, cancer risk can vary dramatically. Changes in composition or structure of bacterial communities in the stomach, either at the time of exposure or over the course of H. pylori infection, may contribute to gastric pathology. In this study, a population of 37 patients from the low-gastric-cancer-risk (LGCR) region of Tumaco, Colombia, and the high-gastric-cancer-risk (HGCR) region of Túquerres, Colombia, were recruited for gastric endoscopy. Antral biopsy specimens were processed for histology and bacterial isolation. Fifty-nine distinct species among 26 genera were isolated by aerobic, anaerobic, and microaerobic culture and confirmed by 16S rRNA analysis. Urease-positive Staphylococcus epidermidis and Streptococcus salivarius were frequently isolated from gastric biopsy specimens. We asked whether coinfection of H. pylori with urease-positive S. salivarius and/or S. epidermidis had a demonstrable effect on H. pylori-induced gastritis in the germfree (GF) INS-GAS mouse model. Coinfections with S. salivarius and/or S. epidermidis did not affect gastric H. pylori colonization. At 5 months postinfection, GF INS-GAS mice coinfected with H. pylori and S. salivarius had statistically higher pathological scores in the stomachs than mice infected with H. pylori only or H. pylori with S. epidermidis (P < 0.05). S. epidermidis coinfection with H. pylori did not significantly change stomach pathology, but levels of the proinflammatory cytokine genes Il-1ß, Il-17A , and Il-22 were significantly lower than in H. pylori-monoinfected mice. This study demonstrates that non-H. pylori urease-positive bacteria may play a role in the severity of H. pylori-induced gastric cancer in humans. IMPORTANCE Chronic infection with H. pylori is the main cause of gastric cancer, which is a global health problem. In two Colombian populations with high levels of H. pylori prevalence, the regional gastric cancer rates are considerably different. Host genetic background, H. pylori biotype, environmental toxins, and dietary choices are among the known risk factors for stomach cancer. The potential role of non-H. pylori gastric microbiota in gastric carcinogenesis is being increasingly recognized. In this study, we isolated 59 bacterial species from 37 stomach biopsy samples of Colombian patients from both low-gastric-cancer-risk and high-gastric-cancer-risk regions. Urease-positive S. epidermidis and S. salivarius commonly cultured from the stomachs, along with H. pylori, were inoculated into germfree INS-GAS mice. S. salivarius coinfection with H. pylori induced significantly higher gastric pathology than in H. pylori-monoinfected mice, whereas S. epidermidis coinfection caused significantly lower H. pylori-induced proinflammatory cytokine responses than in H. pylori-monoinfected mice. This study reinforces the argument that the non-H. pylori stomach microflora play a role in the severity of H. pylori-induced gastric cancer.

Exploiting the Acidic Extracellular pH: Evaluation of Streptococcus salivarius M18 Postbiotics to Target Cancer Cells.

Previously, we showed that the growth, antibiotic resistance, and biofilm formation properties of the pathogens Pseudomonas aeruginosa and Klebsiella pneumonia were tremendously inhibited by the cell-free supernatant of the oral probiotic Streptococcus salivarius M18. These anti-pathogenic activities of the supernatant were more efficient under acidic conditions. The present approach takes advantage of the acidic nature of the tumor microenvironment to evaluate the effect of the S. salivarius M18 postbiotics on colon cancer cells. In both two-dimensional (2D) and three-dimensional (3D) cell culture models, S. salivarius M18 cell-free supernatant showed anti-cancer actions in the pH conditions mimicking the acidity of the tumor. The inhibitory effect was more prominent when the colon cancer cells have been treated with the cell-free supernatant obtained from the inulin incubated S. salivarius M18. The results of this study point out the potential of the S. salivarius M18 functional probiotic products to be used for targeting low pH environments including the unique acidic microenvironment of tumors.

Streptococcus salivarius K12 inhibits Candida albicans aggregation, biofilm formation and dimorphism.

Candida albicans causes candidiasis, particularly in immunocompromised patients. Streptococcus salivarius K12 (K12) is a probiotic isolated from a healthy oral cavity. The study aimed to determine the effect of K12 on C. albicans aggregation, biofilm formation and dimorphism. C. albicans ATCC MYA-4901, acquired immunodeficiency syndrome (AIDS) isolate (ALC2), and oral cancer isolate (ALC3) and K12 were used in the study. All C. albicans strains and K12 were grown in yeast peptone dextrose agar and brain heart infusion agar, respectively, prior to aggregation, biofilm and dimorphism assays. Auto-aggregation of C. albicans MYA-4901 and ALC2 was categorised as high, while the co-aggregation of the strains was low in the presence of K12. C. albicans total cell count decreased significantly when co-cultured with K12 compared with monocultured C. albicans biofilm (p < 0.05). Inhibition of yeast-to-hyphae transition was also observed when co-cultured with K12. In conclusion, K12 inhibits C. albicans aggregation, biofilm formation and dimorphism.

Probiotic Streptococcus salivarius K12 Alleviates Radiation-Induced Oral Mucositis in Mice.

Background: Oral mucositis is the most common oral complication of cancer patients receiving radiotherapy and/or chemotherapy, leading to poor quality of life. Limitations of the current interventions on radiation-induced oral mucositis (RIOM) urge the development of novel therapeutics. Here, we evaluated the treatment outcome of probiotic Streptococcus salivarius K12 on RIOM mice, and oral microbiota that is associated with the progress of RIOM was further investigated. Methods: An experimental RIOM mouse model was established, and S. salivarius K12 was applied to the mouse oral cavity daily. Histological analyses were performed to evaluate the severity of oral mucositis and the treatment outcome of S. salivarius K12. The oral microbiota of mice was further analyzed by 16S rRNA sequencing, microbial culture and qPCR. Results: Irradiation induced conspicuous mucositis in the oral cavity of mice. S. salivarius K12 treatment was beneficial for the healing of RIOM, as reflected by reduced ulcer size, increased basal layer epithelial cellularity and mucosal thickness, and elevated epithelial proliferation and attenuated apoptosis. RIOM mice presented significant oral microbial dysbiosis, with an overgrowth of oral anaerobes. S. salivarius K12 treatment reconstituted the oral microbiota and decreased the abundance of oral anaerobes of RIOM mice. In addition, S. salivarius K12 treatment inhibited NI1060 in Pasteurella genus and downregulated the expression of nitrate reductase. Conclusions: S. salivarius K12 treatment can alleviate RIOM and reconstituted the dysbiotic oral microbiota in mice. S. salivarius K12 may represent a promising adjuvant treatment to improve the quality of life of cancer patients receiving radiotherapy.

Streptococcus salivarius Isolates of Varying Acid Tolerance Exhibit F1F0-ATPase Conservation.

Genes encoding the subunits of the membrane-bound F1F0-ATPase (responsible for exporting protons from the cytoplasm and contributing to acid tolerance) were sequenced for 24 non-mutans streptococci isolated from carious lesions. Isolates, mostly Streptococcus salivarius, displayed a continuum of acid tolerance thresholds ranging from pH 4.55 to 3.39, but amino acid alignments of F1F0-ATPase subunits revealed few non-synonymous substitutions and these were unrelated to acid tolerance. Thus, the F1F0-ATPase is highly-conserved among S. salivarius isolates despite varying acid tolerance thresholds, supporting the contention that acid tolerance is determined by the level of gene/protein expression rather than variation in molecular structure.

Bactericidal effect of Er,Cr:YSGG laser irradiation on endodontic biofilm: An ex vivo study.

AIM: This ex vivo study aimed to evaluate the of Er,Cr:YSGG laser effectiveness in the decontamination of an endodontic biofilm. MATERIALS AND METHODS: Seventy-three single rooted human teeth, freshly were chosen. Each tooth was exposed to four associated species in an endodontic biofilm (Enterococcus faecalis, Streptococcus salivarius, Porphyromonas gingivalis, and Prevotella intermedia) and randomly allocated to one of the seven experimental groups. The group 1 (7 teeth) was used to finalize the reliable biofilm-forming technique. The groups 2 and 3 (15 teeth each group) were irradiated with two different Er;Cr:YSGG laser settings (0,75 W - 40 Hz and 4 W - 40 Hz, respectively). The groups 4 and 5 (15 teeth each group) were irrigated with two different solutions and laser irradiated with the same settings (1,5 W - 15 Hz). The group 6 (6 teeth) was the control group treated only with 4 ml 2,5% NaOCl irrigation during 60 s. RESULTS: The observations of group 2 and 3 specimens showed the ripeness of the biofilm with the presence of Enterococcus faecalis and Streptococcus salivarius in chains but in group 3 thermal edge effects produced by the optic fiber in the canal walls were present. The group 4 specimens observation showed an average cleaning of the root canal walls while on the canal walls of group 5 samples the apical third presented several debris and smear layer and in the centre cracks and melting dentin of the radicular wall were observed. CONCLUSION: In those experimental conditions, this study, demonstrated that Er,Cr:YSGG laser has a canals decontamination ability when associated to NaOCl irrigation.

Randomised, double-blind, placebo-controlled trial of oral probiotic Streptococcus salivarius M18 on head and neck cancer patients post-radiotherapy: a pilot study.

Xerostomia detrimentally affects the oral health of many head and neck cancer patients who undergo radiotherapy. Its sequelae become an ongoing burden for patients that often manifest as periodontal disease and dental decay. Bacteria play a major role in the pathogenesis of these conditions and here we explore the use of an oral probiotic to beneficially modulate the oral bacterial community post-radiotherapy. In this pilot study, a four-week intervention with oral probiotic lozenges containing Streptococcus salivarius M18 was trialled in seven patients. Post-intervention changes in oral health and in the composition of the plaque and saliva bacterial communities were compared with six patients in a placebo group. An improvement in periodontal screening and plaque index scores was observed in both groups after the intervention period. The oral probiotic lozenges did not significantly impact bacterial community composition or diversity, nor did the probiotic lozenges increase the relative sequence abundance of ZOTU_1 (the probiotic-associated sequence assigned to S. salivarius) detected in the samples. Network analyses suggest negative interactions occurred between ZOTU_1 and species from the periopathogenic genera Campylobacter, Fretibacterium, Selenomonas and Treponema but further investigation is required to more fully understand the beneficial properties of this oral probiotic.

Alteration of Streptococcus salivarius in Buccal Mucosa of Oral Lichen Planus and Controlled Clinical Trial in OLP Treatment.

Oral lichen planus (OLP) is a T cell-mediated common chronic inflammatory mucosal disease, with limited therapies available for long-term use. Previous study showed that ratio of genus Streptococcus decreased significantly in OLP patients when compared with controls. Buccal cotton swab samples of 43 OLP patients and 48 healthy individuals were collected for real-time quantitative polymerase chain reaction (RT-PCR) to investigate relative abundance alteration of Streptococcus salivarius in OLP lesions. Bacterial supernatants of S. salivarius ATCC® BAA-2593™ were collected by centrifugation and added to HSC-3 cells, and quantitative analysis of expression of IL-1ß, IL-6, IL-8, and TNF-α in the HSC-3 cells was determined by RT-PCR. Then, a randomized, non-blinded, controlled study was conducted. Forty patients with symptomatic OLP were randomly allocated into two groups and received topical treatment of 0.1% triamcinolone acetonide dental paste (group A) and S. salivarius K12 lozenge (group B), respectively, for 4 weeks. Sign scores, visual analogue scale (VAS), and adverse reactions were recorded. Relative abundance of S. salivarius in the OLP group was lower than that of control group (P < 0.05). After treated with 0.1% supernatants of S. salivarius ATCC® BAA-2593™, the expression level of IL-6 in the HSC-3 cells significantly reduced (P < 0.001), while IL-1ß, IL-8, and TNF- α showed a decreasing tendency (P > 0.05). There was significant reduction in sign scores and VAS scores in both groups after the 4-week treatment, with no significant difference between two groups. No adverse reaction was observed. S. salivarius might maintain local immune balance by inhibiting the NF-κB pathway. Topical application of Streptococcus salivarius K12 seemed to be effective in treatment of symptomatic OLP, especially with promising potential in long-term use. More detailed clinical studies with long follow-up period and standardized usage/dosage are expected to acquire definite conclusions.

Enzymatic polymerization derived engineered polysaccharides as reinforcing fillers of ethylene vinyl acetate composites.

A novel monomer based, controlled enzymatic polymerization was employed to produce an engineered alpha-1,3 glucan polysaccharide. The structure and material properties of the engineered polysaccharide were characterized using various techniques. The use of such engineered polysaccharide as a reinforcing filler of polymers was evaluated using model polymers. For this, the alpha-1,3 glucan was incorporated into ethylene vinyl acetate co-polymer (EVA) matrices with vinyl acetate content of 32% and 40% via a melt processing fabrication process. Various mechanical and rheological properties of the fabricated composites were evaluated. The effect of vinyl acetate content of the EVA resin on the interaction with alpha-1,3 glucan that result in various performances attributes was also investigated and reported. The incorporation of alpha-1,3 glucan in these EVA composites resulted in the improvement of key composite properties, such as toughness, modulus, wear resistance, and hardness showing the reinforcing potential of these engineered polysaccharides.

Chemical Composition, Antibacterial and Antifungal Potential of an Extract From the Leaves of Guapira Graciliflora Mart. Against Oral Microorganisms of Dental Interest

Abstract Objective: To perform an in vitro analysis of antibacterial and antifungal potential of an alcoholic extract from the leaves of Guapira Graciliflora Mart. against oral microorganisms and determine its chemical composition. Material and Methods: A hydroalcoholic extract of the leaves form G. graciliflora was obtained through maceration, vacuum concentration and freeze-drying. Antibacterial and antifungal activities were evaluated against Streptococcus mutans, Streptococcus salivarius, Streptococcus oralis, Streptococcus parasanguinis, Streptococcus mitis and strains of Candida albicans using broth microdilution method. Phytochemical analysis determined the total phenolic compounds, protein concentration and total of sugars present in the extract. Results: G. Graciliflora demonstrated antifungal activity against the LM 11 and LM 410 clinical isolates of C. albicans (MIC 0.5 mg/mL and 2 mg/mL, respectively). The other microorganisms tested were resistant to the extract. The phytochemical analysis revealed 3% proteins, 13% total sugars and 17% phenolic compounds. Conclusion: G. Graciliflora has antifungal activity against clinical strains of C. albicans and exhibits proteins, sugars and phenolic compounds in its chemical composition.

Elaboração e caracterização de iogurte saborizado com polpa de oiti (Licania tomentosa)

Objetivou-se elaboração e caracterização de iogurte saborizado com polpa de oiti (Licania tomentosa). Foram produzidos quatro formulações com diferentes concentrações da polpa de oiti. Os parâmetros físico-químicos foram pH, Acidez em ácido lático, Umidade, Atividade de água (Aw), Cinzas, Lipídeos, Proteínas, Sólidos Solúveis Totais (ºBrix), Carboidratos totais, Valor Calórico (Kcal), Açúcares Redutores, Açúcares não redutores e Açúcares Totais. As análises microbiológicas foram realizadas durante 21 dias de armazenamento. As análises físico-químicas foram submetidos à análise de variância (ANOVA) e ao teste de Tukey. As análises microbiológicas atenderam aos limites estabelecidos pela legislação. E os iogurtes apresentaram dentro dos padrões, sendo uma opção para a região produtora dessa fruta.

The efficacy and tolerability of Streptococcus salivarius 24SMB and Streptococcus oralis 89a administered as nasal spray in the treatment of recurrent upper respiratory tract infections in children.

OBJECTIVE: Nasal administration of Streptococcus salivarius 24SMB and Streptococcus oralis 89a has been proposed to reduce the risk of new episodes of adenoiditis, tonsillitis and acute rhinosinusitis in children. PATIENTS AND METHODS: We enrolled 202 children with a recent diagnosis of recurrent upper respiratory tract infection. All the patients were treated twice daily for 7 days each month for 3 consecutive months with a nasal spray whose active agents were two specific bacterial strains: Streptococcus salivarius 24SMB and Streptococcus oralis 89a. Evaluation was performed at the end of treatment and at follow-up at 3, 6, and 12 months. RESULTS: Patients who completed the entire 90-day course of bacteriotherapy and the follow-up period showed a 64.3% reduction in their episodes of upper respiratory tract infections compared to the number of episodes recorded in the previous year. Treatment decreased the reported incidence of infection events by 52.4% in the first 3 months, 31.2% at 6-month follow-up, and 20.8% after 12 months. Enrolled patients tolerated the product well, and there were no dropouts. CONCLUSIONS: Prophylactic bacteriotherapy by administration of Streptococcus salivarius 24SMB and Streptococcus oralis 89a in children with a history of recurrent upper respiratory tract infection could reduce the number of episodes of otolaryngologic infections. Bacteriotherapy can be even more clinically important due to increasing difficulty in finding new effective antibiotic compounds. New alternative therapeutic approaches must be found with, in comparison to antibiotics, greater specificity and safety with respect to patients' native beneficial flora; lack of drug interactions; the ability to leverage complementary systemic modes of action; and drastically reduced risk of developing resistance within the patient population and the environment.