Nitropropenyl Benzodioxole, An Anti-Infective Agent with Action as a Protein Tyrosine Phosphatase Inhibitor

Abstract

We report on the activities of a broad spectrum antimicrobial compound,nitropropenyl benzodioxole (NPBD) which are of relevance to its potential as an anti-infective drug. These investigations support the proposal that a major mechanism of NPBD is action as a tyrosine mimetic, competitively inhibiting bacterial and fungal protein tyrosine phosphatases (PTP).NPBD did not affect major anti-bacterial drug targets, namely, ATP production, cell wall or cell membrane integrity, or transcription and translation of RNA. NPBD inhibited bacterial YopH and human PTP1B and not human CD45 in enzyme assays. NPBD inhibited PTP-associated bacterial virulence factors, namely, endospore formation in Bacillus cereus, prodigiosin secretion in Serratia marcescens, motility in Proteus spp., and adherence and invasion of mammalian cells by Yersinia enterocolitica. NPBD acts intracellularly to inhibit the early development stages of the Chlamydia trachomatis infection cycle in mammalian cells known to involve sequestration of host cell PTPs. NPBD thus both kills pathogens and inhibits virulence factors relevant to early infection, making it a suitable candidate for development as an anti-infective agent, particularly for pathogens that enter through, or cause infections at, mucosal surfaces. Though much is yet to be understood about bacterial PTPs, they are proposed as suitable anti-infective targets and have been linked to agents similar to NPBD. The structural and functional diversity and heterogeneous distribution of PTPs across microbial species make them suitably selective targets for the development of both broadly active and pathogen-specific drugs.

Crystal Structure of (<i>E</i>)-1-(3,4-Methylenedioxy-6-fluorophenyl)-2-nitropropene

“…2,3 More recently, a series of new β-nitrostyrene derivatives have been developed as antibacterial agents. 4 In this last approach, the β-nitrostyrene compounds generally displayed a lower activity towards bacteria relative to the β-methyl-βnitrostyrene analogues. 4 Consequently, the β-methyl-βnitrostyrene scaffold represents a putative pharmacophore for antibacterial activity.…”

Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets

“…NPBD was equally effective against a C. jejuni LOS deficient mutant and the parent strain. NPBD does not alter membrane permeability of E. coli or damage spheroplasts of E. coli and M. catarrhalis [ 12 ]. NPBD MIC/MBC for antibiotic-resistant clinical isolates of S. aureus , E. faecalis , E. faecium , P. mirabilis , E. coli and C. jejuni were similar to those of laboratory strains suggesting no cross resistance to the classes of antibiotics tested ( Table 1 ).…”

“…and to respiratory tract pathogens H. influenzae , S. pneumoniae, S. pyogenes , M. catarrhalis , N. meningitidis and Acinetobacter species. It inhibits urogenital pathogens Chlamydia trachomatis [ 12 ] and Candida albicans [ 15 ] and respiratory pathogen M. tuberculosis ( Table S10 ). For skin and mucosal infections where higher concentrations are achievable it could be an effective antimicrobial agent.…”

“…NPBD also inhibits virulence factors in vitro; prodigiosin production in Serratia marcescens , cell adherence and invasion by Y. enterocolytica and motility in Proteus spp. [ 12 ]. Inhibition of virulence factors would contribute to infection control at skin and mucosal surfaces.…”

“…Nitropropenyl benzodioxole (NPBD) is a lipophilic, cell permeable, neutral tyrosine mimetic, belonging to the family of nitroalkenyl benzenes (NAB) ( Figure 1 ; Supplementary Materials Figure S1 and Table S1 ). Nitroethenyl benzene (NEB), nitropropenyl benzene (NPB), nitroethenyl benzodioxole and NPBD are reversible inhibitors of enzymatic activity of PTP1B, SHP1, Yop and CD45 with differing levels of inhibition of enzymatic function ([ 11 , 12 , 13 ], Table S2 ). These compounds compete with PTyr substrate proteins for binding to PTP active sites.…”