STANISLAW WNUK

Abstract

As antimicrobial resistance is a growing global threat, it is imperative to develop alternative therapeutic approaches. Quorum sensing (QS) is a type of bacterial cell-to-cell signaling pathway mediated through the production, release, and detection of the small signaling molecules called autoinducers (AIs). Such communication allows bacterial control of crucial function including virulence factors and biofilm formation. If achieved, the inhibition of QS would reduce bacterial pathogenicity, thus providing disease prevention and treatment. The most common QS signaling molecule used by Gram-negative bacteria are acylhomoserine lactones (AHLs). The development of non-native acylhomoserine lactone (AHL) ligands has emerged as a promising new strategy to inhibit QS in Gram-negative bacteria. FIU inventors have developed new optically pure γ-lactams and cyclic azahemiacetals, bearing alkylthiomethyl substituents with different carbon chain lengths that are capable of inhibiting bacterial QS pathways. These compounds have shown inhibition of the pathogenicity of Gram-negative bacteria such as Pseudomonas aeruginosa, an important human opportunistic pathogen affecting immunocompromised individuals, cancer patients, burn victims, cystic fibrosis patients, and patients with impaired lung function.

Benefit

• Effective against drug resistant bacterial strains • Attenuate infection without the creation of resistant bacteria or adverse effects • Can be used in combination with antibiotics

Market Application

Treatment and prevention of infections caused by Gram-negative bacteria in human, animals and plantsSurface treatment of surgical instruments, medical and healthcare devices, food processing, water treatment, and agriculture equipment, boat hull, and power generating machinery and equipment

Abstract

The dramatic increase in bacterial resistance to antibiotics is a grave threat to global health. A dearth of new antibiotics has fostered the emergence and worldwide spread of multidrug resistant (MDR) bacteria, resulting in an increase of serious infections with high mortality rates. To overcome this serious health concern, discovery and development of new antibiotics are urgently needed. Arsinothricin [2-amino-4-(hydroxymethylarsinoyl)-butanoic acid or AST] has broad spectrum antibiotic activity and is effective against both Gram-positive and Gram-negative bacteria, including carbapenem-resistant Enterobacter cloacae (CRE), one of the World Health Organization critical priority pathogens, and Mycobacterium bovis BCG, a causative agent of animal tuberculosis that is closely related to the human pathogen MTB. AST is produced by the rice rhizosphere bacterium Burkholderia gladioli GSRB05. However, the amounts of AST produced by such bacterium are insufficient for further biochemical and clinical characterization of this antibiotic and for development of more effective derivatives. Overcoming this obstacle requires a chemical synthetic process.FIU inventors have developed methods for the semi-synthesis of the antibiotic AST and derivatives. These methods comprise steps for synthesizing the precursor of AST, hydroxyarsinothricin [2-amino-4-(dihydroxyarsonoyl)butanoic acid or AST-OH], and steps of converting AST-OH to AST through an enzymatic methylation of AST-OH. Advantageously, it is anticipated that both the chemical synthesis and enzymatic methylation can be scaled up to produce AST and its derivatives in amounts sufficient for further drug development.

Benefit

Provides a simple synthesis method of AST-OH and its derivativesCan be scaled up to produce AST and its derivatives in amounts sufficient for further drug developmentEliminates the necessity of conversion of pentavalent arsenic acids with toxic SO2 gas, and challenging displacement of hydroxyl group with chloride

Market Application

Drug development: antibacterial candidates against bacterial species from both Gram-positive and Gram-negative

Publications

Semisynthesis of the Organoarsenical Antibiotic Arsinothricin J. Nat. Prod. 2020, 83, 9, 2809–2813

Abstract

Haloindenes are convenient precursors in organic and biologically targeted syntheses. Although there are several reports for the synthesis of 5- or 6-chloro- and bromoindenes, there is only one method for the preparation of more reactive 5- or 6-iodoindene which requires expensive intermediates and several steps. Furthermore, reported yields for 5- or 6-iodoindenes obtained by the reduction of the corresponding 5- or 6-nitroindene followed by diazotization-iodination of the resulting unstable 5- or 6-aminoindene were only 20% and 7%. FIU inventors have developed expedited synthesis of 5, 6, and 7-iodoindenes from the corresponding aminoindan-1-ones in more than 70% yield, employing readily available precursors and reagents. A three-step sequence involves diazotization-iodination of 5 aminoindan-1-one followed by reduction and dehydration. The method has a general character and can be extended for the preparation of various 4-, 5-, 6- or 7-haloindenes using different halogen sources for diazotization-halogenation reaction.

Benefit

Preparation of expensive 5-iodoindene and unreported 7-iodoindene in high yields utilizing readily available and cost-effective reagentsAvoids the use of expensive nitroindenes, unstable aminoindenes, and potentially explosive trifluoroperacetic acidCan be extended for the preparation of various 4-, 5-, 6- or 7-haloindenes

Market Application

Precursors in organic and biologically targeted syntheses

Publications

A. Hasan Howlader, Keili Diaz, Alexander M. Mebel, Ralf I. Kaiser, Stanislaw F. Wnuk, Iodoindenes: Synthesis and application to cross-coupling, Tetrahedron Letters, Volume 61, Issue 43, 2020, 152427, ISSN 0040-4039