The Bactericidal Tandem Drug, AB569: How to Eradicate Antibiotic-Resistant Biofilm Pseudomonas aeruginosa in Multiple Disease Settings Including Cystic Fibrosis, Burns/Wounds and Urinary Tract Infections

Abstract

The life-threatening pandemic concerning multi-drug resistant (MDR) bacteria is an evolving problem involving increased hospitalizations, billions of dollars in medical costs and a remarkably high number of deaths. Bacterial pathogens have demonstrated the capacity for spontaneous or acquired antibiotic resistance and there is virtually no pool of organisms that have not evolved such potentially clinically catastrophic properties. Although many diseases are linked to such organisms, three include cystic fibrosis (CF), burn/blast wounds and urinary tract infections (UTIs), respectively. Thus, there is a critical need to develop novel, effective antimicrobials for the prevention and treatment of such problematic infections. One of the most formidable, naturally MDR bacterial pathogens is Pseudomonas aeruginosa (PA) that is particularly susceptible to nitric oxide (NO), a component of our innate immune response. This susceptibility sets the translational stage for the use of NO-based therapeutics during the aforementioned human infections. First, we discuss how such NO therapeutics may be able to target problematic infections in each of the aforementioned infectious scenarios. Second, we describe a recent discovery based on years of foundational information, a novel drug known as AB569. AB569 is capable of forming a “time release” of NO from S-nitrosothiols (RSNO). AB569, a bactericidal tandem consisting of acidified NaNO2 (A-NO2–) and Na2-EDTA, is capable of killing all pathogens that are associated with the aforementioned disorders. Third, we described each disease state in brief, the known or predicted effects of AB569 on the viability of PA, its potential toxicity and highly remote possibility for resistance to develop. Finally, we conclude that AB569 can be a viable alternative or addition to conventional antibiotic regimens to treat such highly problematic MDR bacterial infections for civilian and military populations, as well as the economical burden that such organisms pose.

Investigation of blaIMP-1, blaVIM-1, blaOXA-48 and blaNDM-1 carbapenemase encoding genes among MBL-producing Pseudomonas aeruginosa

“…Pseudomonas aeruginosa can be defined as one of the major causes of severe infections like systemic pneumonia, burns, cystic fibrosis, skin inflammation and some infections related to respiratory tract, urinary tract, soft tissue bone and joint, gastrointestinal, blood and cornea, bacteremia, septicemia infections especially in patients with neutropenia and transplantation (Barry et al,2021;Hassett et al, 2021). The species need narrow nutrition requirements and withstand in harsh environmental conditions.…”

Transnitrosation of Alicyclic N-Nitrosamines Containing Sulfur Atoms in Five- or Six-Membered Rings

“…19 Compound 6 reacted with (Boc)2O to give t-butyl 4-carbamoyl-1,3-thiazinane-3-carboxylate (7). t-Butyl 4-carbamothioyl- Thiomorpholine-3-carboxylic acid was prepared from cysteine as described by Shiraiwa et al 22 Thiomorpholine-3-carboxylic acid was protected by treatment with (Boc)2O, amidated by aqueous ammonia solution with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt), followed by thioamidation with P2S5 under ultrasonication to obtain t-butyl 3-carbamothioylthiomorpholine-4-carboxylate (9). Compound 9 was deprotected and nitrosation according to the same procedure described above to obtain 3 (Scheme 2).…”

“…1,2 NO plays important roles in mammalian physiology and is synthesized in vivo via the activity of NO synthases. [3][4][5] NO plays particularly important roles in biological processes such as blood pressure regulation by modulating vascular relaxation 2,[5][6][7] as well as in immune responses 8,9 and neural signal transduction. 10,11 S-Nitrosothiols (RSNOs) function as NO transporters in vivo and routinely serve as donors of NO bioactivity.…”

“…RSNOs have been studied as NO donors for therapeutic agents, 6,7,12 and have exhibited potential in the treatment of cardiovascular disorders and infectious diseases as well as the regulation of blood pressure. 6,9,13,14 Notably, S-nitrosoglutathione (GSNO), which is the product of S-nitrosation of the abundant intracellular antioxidant glutathione, has been detected in vivo. Despite a half-life measured in hours, the stability of RSNO is reduced by enzymatic and non-enzymatic degradation, rendering it too low for clinical application.…”

Effect of Sulfur-Containing Side Chains on Transnitrosation of N-Nitroso Compounds of Thiazolidines

“…Nitric oxide (NO) is a cell transmitter synthesized in vivo from arginine via NO synthase. [1][2][3] NO is involved in many biological processes, including vasodilation, [4][5][6] inhibition of platelet aggregation, 3,7 immune responses, 8,9 and nerve signal transduction. 10,11 Due to its chemical reactivity, NO has a short half-life (5-10 seconds).…”