The Activity of Provectus’s Rose Bengal Sodium Drug Substance Against Colistin-Resistant Gram-Negative Bacteria
RBS is a potential broad-spectrum anti-bacterial agent for MDR G+ bacteria, and MDR G- bacteria in combination with an anti-G- drug
In September 20201, Provectus established an infectious disease-directed, sponsored research relationship, program, and agreement (SRA) with Michio Kurosu, PhD, Professor, Department of Pharmaceutical Sciences at the College of Pharmacy of the University of Tennessee Health Science Center (UTHSC) in Memphis. The goal of this Provectus-UTHSC applied research program – one of several nodes of Provectus’ distributed research network of academic medical centers conducting preclinical research on Provectus’ pharmaceutical-grade rose bengal sodium (RBS) drug substance (RBS DS) – was to investigate RBS’ potential targeting of multi-drug resistant (MDR) bacteria.
Dr. Kurosu and his colleagues published their first paper from this research, entitled “Antibacterial Activity of Pharmaceutical-Grade Rose Bengal: An Application of a Synthetic Dye in Antibacterial Therapies” (open access) in January 2022. The paper showed RBS’ activity against MDR gram-positive (G+) bacteria and, in a novel manner, activity against biofilms.
On Thursday, Provectus press released the publication of a second journal article by Dr. Kurosu and his colleagues about their preclinical research on Provectus’ RBS against colistin-resistant gram-negative (G-) bacteria. The article was entitled “Antibacterial effect of rose bengal against colistin-resistant gram negative bacteria” (subscription required).
Provectus Substack Post Short-Form
“Antibiotic resistance is a growing world health threat. More than 2.8 million infections resistant to antimicrobials — which include antibiotics as well as antifungals and antiseptics — take place in the U.S. each year, and more than 35,000 people die as a result, according to estimates by the Centers for Disease Control and Prevention.”2 “Colistin is presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms…”3
A formulation of Provectus’ RBS DS effectively inhibited the growth of colistin-resistant G- bacteria. RBS also possesses a rapid-killing feature for the bacteria.
Provectus’ RBS DS may support the development of a broad-spectrum, rapid-acting, likely topically-applied [for now] drug product candidate for skin, oral, and surgical wound infections.
Provectus Substack Post Long-Form
At the time that this infectious disease-directed SRA was first established, Dr. Kurosu and his colleagues planned to undertake in vitro studies on the spectrum of RBS activity against drug-susceptible and drug-resistant bacterial strains, synergistic activity of combinations of RBS and U.S. Food and Drug Administration- (FDA-) approved antibiotics for G- bacteria, the mutation frequency of RBS against bacterial strains, measurement of spontaneous bacterial mutations for RBS and these combinations, and gene analyses of mutant bacterial strains to understand resistance mechanisms.
In both articles, Dr. Kurosu and his colleagues abbreviated the formulation of Provectus’ pharmaceutical-grade, high-purity, RBS drug substance that they used as “HP-RBf.” We will use RBS, RBS DS, and HP-RBf interchangeably in this Provectus Substack post. Readers should consider them interchangeable in regards to Provectus’ drug discovery and clinical development work. An image of the abstract of the second article is below.
Dr. Kurosu and his colleagues’ two key results were:
(1) HP-RBf effectively inhibits the growth of the colistin-resistant Gram-negative bacteria
A sample portion of their Table 2 is the below image.
(2) HP-RBf possesses a rapid-killing feature for colistin-resistant Gram-negative bacteria
Their Figure 1 is the below image.
A related note from the new Kurosu et al. article:
“We have reported photodynamic growth inhibitions of HP-RBf against Gram-positive bacteria; the addition of HP-RBf in the bacterial cultures (1.3–4.6 × 108 CFU•ml-1) of Gram-positives including drug-resistant strains could cause a greater than 6-log reduction of bacterial cells in less than 2 min [35].”
Article Summary
Dr. Kurosu and his colleagues concluded:
“In summary, our studies reported here suggest that HPRBf is a promising drug candidate to treat intrinsic and acquired colistin-resistant Gram-negative superficial bacterial infections. Colistin-resistant Gram-negative bacteria involve membrane structural modifications that lead to the resistance to important antibacterial agents used for treating Gram-negative bacterial infections [40, 41]. Interestingly, these structural changes make HP-RBf more susceptible to colistin-resistant Gram-negative bacteria. We reported previously that HP-RBf does not change the integrity of human skin tissue at 200 μM (203.4 μg•ml–1) concentration under the fluorescent light for 1 h [35]. Therefore, the selectivity index and therapeutic index of HP-RBf for topical application are very high. Our toxicology studies showed that HP-RBf does not have systemic toxicological effects, mutagenic potential, and female reproductive and development effects at the therapeutic concentrations [42, 43]. To put it all together, HP-RBf is an attractive drug candidate as a rapid bactericidal agent that can be applied to skin, oral, and surgical wound infections. HP-RBf has the potential to serve as a broad-spectrum anti-bacterial agent for Gram-positive bacteria (previous studies), and Gram-negative bacteria (this study) in combination with an anti-Gram-negative drug.”
Closing remarks
Provectus is more than the “just-a-melanoma-company” direction of its prior existence and prior management.4 Much more. Without a doubt, Provectus’ most mature area of clinical development, and thus our lead disease area and primary area of expertise, is broadly oncology and specifically injectable solid tumor cancers (i.e., intralesional or intratumoral therapy), where more than 450 patients have been treated with investigational small molecule cancer immunotherapy PV-10 for cutaneous and visceral lesions, in monotherapy and combination therapy settings, via clinical trials5, investigator-initiated studies6, expanded access programs7, and quality-of-life study8. Furthermore, Provectus’ primary focus is on the regulatory and clinical advancement of PV-10’s drug development program, particularly as it relates to designing and initiating cancer combination therapy clinical trials that can show clinical benefit against first- or second-line standards of care (whether actual or historical control arms).
We also believe that Provectus has potentially established itself as the only source of FDA-approvable RBS DS and, from regulatory and chemical analytical perspectives, that current commercial- or non-pharmaceutical grades of rose bengal lack pharmaceutical relevance.
The core of our business strategy is indeed to advance PV-10 towards regulatory and commercial validation in oncology. Yet, an important piece of Provectus’ overall business strategy comprises sufficiently investigating, validating, and potentially monetizing RBS DS’ opportunities to power the development of different formulations for different investigational drugs to treat a myriad of different disease areas and diseases by Provectus and/or other drug developers.
Provectus historically referred to its rose bengal molecule and pharmaceutical-grade drug substance as “rose bengal disodium.” In November 2022, Provectus announced that the International Nonproprietary Names (INN) Expert Committee of the World Health Organization (WHO) had selected “rose bengal sodium” (RBS) for the nonproprietary name of Provectus’ drug substance and active pharmaceutical ingredient (API).
Wigglesworth, Alex. Discovery of antibiotic-resistant superbugs in L.A. wastewater sparks worry. Los Angeles Times, April 10, 2023.
Andrade FF, Silva D, Rodrigues A, Pina-Vaz C. Colistin Update on Its Mechanism of Action and Resistance, Present and Future Challenges. Microorganisms. 2020 Nov 2;8(11):1716.
For historical context, a “group” of stockholders (i.e., PRH) entered into a Definitive Financing with the Company in 2017. PRH, then and now, specifically disclaims that it was or is a “group” as defined in U.S. federal securities laws.
Three monotherapy Phases 1-3 trials and one combination therapy Phase 1b trial with three distinct patient cohorts for metastatic cutaneous melanoma, and two monotherapy and combination therapy Phase 1 trials for cancers of the liver (nine different histologies, including pancreatic ductal adenocarcinoma).
One monotherapy Phase 1 trial focused on mechanism of action and one combination therapy Phase 2 trial for cutaneous melanoma (PV-10 + radiotherapy that yielded a journal publication).
A multi-country, multi-site intermediate-sized program for cutaneous melanoma that yielded three journal publications, and multiple single-patient combination therapy treatments.
A multi-country, multi-site study of patients with metastatic cutaneous melanoma that yielded a journal publication.