Disease relevance of Bicozamycin

• Studies of changes in predominant aerobic fecal flora among the 11 subjects treated with bicozamycin showed the appearance of only one highly resistant Citrobacter freundii at the end of 1 wk of therapy and only a total of six resistant isolates at the end of 3 wk [1].
• Treatment failed in significantly fewer patients treated with bicozamycin than those treated with placebo when diarrhea was associated with Shigella, Salmonella or toxigenic E. coli [2].
• The mean duration of illness was shorter in the bicozamycin than the placebo treatment groups for patients with diarrhea due to Shigella (37 versus 96 hours; p = 0.01), toxigenic Escherichia coli (31 versus 60 hours; p = 0.003), and unknown pathogens (18 versus 41 hours; p = 0.02) [2].
• Bicyclomycin is a commercially important antibiotic that has been shown to be effective against many gram-negative bacteria [3].
• Our results explain the lack of activity of bicyclomycin against many gram-positive bacteria and raise the possibility that the essentiality of rho may be the exception rather than the rule [4].

High impact information on Bicozamycin

• Bicyclomycin, a specific inhibitor of Rho, increased the tight ATP binding and was used to calibrate ATP-induced fluorescence quenching by using [gamma-(32)P]ATP filter binding [5].
• Evidence for the location of bicyclomycin binding to the Escherichia coli transcription termination factor Rho [6].
• The interaction of Rho and the antibiotic bicyclomycin was probed using in vitro transcription termination reactions, poly(C) binding assays, limited tryptic digestions, and the bicyclomycin inhibition kinetics of ATPase activity in the presence of poly(dC) and ribo(C)10 [7].
• The approximate I50 value for the bicyclomycin inhibition of transcription termination at Rho-dependent sites within a modified trp operon template was 5 microM [7].
• Biochemical studies indicate that the M. luteus protein is very similar to E. coli Rho in terms of its RNA-dependent NTPase activity and its sensitivity to the Rho-specific inhibitor bicyclomycin [8].

Chemical compound and disease context of Bicozamycin

• Bicyclomycin exhibited inhibitory effects on the exclusive biosynthesis of the lipoprotein in histidine-starved cells of E. coli 15 THU [9].

Biological context of Bicozamycin

• The antibiotic bicyclomycin affects the secondary RNA binding site of Escherichia coli transcription termination factor Rho [7].
• Previous studies have shown that bicyclomycin binds near the ATP hydrolysis pocket on rho [10].
• We show here that termination is Rho dependent and is suppressed in a rho mutant or by bicyclomycin treatment when fimE mRNA is expressed by the fimE gene, either from a multicopy recombinant plasmid or in its native chromosomal location [11].
• Either a multicopy supply of the rof gene or bicyclomycin, both of which inhibit the transcription termination Rho factor, suppressed the increased sensitivity to oxidative stress of the rifampicin-resistant rpoB mutation in Escherichia coli [12].
• Our results show that bicyclomycin impairs the normal breakage of that interpeptidic bond, whose cleavage is needed for the normal remodeling of peptidoglycan and cell growth [13].

Associations of Bicozamycin with other chemical compounds

• Preliminary mechanistic information has been obtained by monitoring the polyC-dependent ATPase activity of rho in the absence and presence of bicyclomycin and dihydrobicyclomycin [14].
• Treatment failures were unusual with TMP-SMZ, TMP, and bicozamycin therapy (5% vs. 39% for the placebo-treated students) [15].

Gene context of Bicozamycin

• Resistance to teicoplanin rose 4-fold by insertional inactivation of tcaA or by deletion of the entire operon. tcaA encodes a hypothetical transmembrane protein with a metal-binding motif, possibly a sensor-transducer. tcaB codes for a membrane-associated protein, which has sequence homologies to a bicyclomycin resistance protein [16].
• The antibiotic bicyclomycin inhibited the in vitro RNA-dependent ATPase activity of Rho 77, did not inhibit growth of streptomycetes but delayed the development of aerial mycelia [17].
• The strain containing the G337S Rho mutation also has high bicyclomycin resistance, and the proximity of L208, S266 and G337 in the quaternary structure of the Rho model has enabled a candidate bicyclomycin-binding pocket to be delineated [18].
• All but one of the resistant mutants displayed greatly increased tna operon expression when grown in the presence of bicyclomycin [19].
• In this study we describe BI-K0058, a new inhibitor of the transcription-termination factor Rho belonging to a different chemical class from bicyclomycin, the only known antibiotic acting on Rho [20].

Analytical, diagnostic and therapeutic context of Bicozamycin

• The efficacy of bicozamycin, a poorly absorbable antibiotic, in the treatment of acute diarrhea was assessed in a prospective, double-blind study of 140 adults from the United States visiting Guadalajara, Mexico. Patients randomly received bicozamycin (500 mg orally four times daily) or placebo for 3 days [2].
• Development of a technique to determine bicyclomycin-rho binding and stoichiometry by isothermal titration calorimetry and mass spectrometry [21].
• In one instance, the racemic analogue 10c (R1 = CH2Ph, R2 = OH, R3 = H) showed interesting antimicrobial activity against several Gram-positive organisms; the minimum inhibitory concentrations were of the same order of magnitude as bicyclomycin displays toward Gram-negative organisms [22].

References