Flavomycin restores colistin susceptibility in multidrug-resistant Gram-negative bacteria.

Polymyxin is used as a last resort antibiotics for infections caused by multi-drug resistant (MDR) Gram-negative bacteria and is often combined with other antibiotics to improve clinical effectiveness. However, the synergism of colistin and other antibiotics remains obscure. Here, we revealed a notable synergy between colistin and flavomycin, which was traditionally used as an animal growth promoter and has limited activity against Gram-negative bacteria, using checkerboard assay and time-kill curve analyses. The importance of membrane penetration induced by colistin was assessed by examining the intracellular accumulation of flavomycin and its antimicrobial impact on Escherichia coli (E. coli) strains with truncated lipopolysaccharides. Besides, a mutation in the flavomycin binding site was created to confirm its role in the observed synergy. This synergy is manifested as an augmented penetration of the E. coli outer membrane by colistin, leading to increased intracellular accumulation of flavomycin and enhanced cell killing thereafter. The observed synergy was dependent on the antimicrobial activity of flavomycin, as mutation of its binding site abolished the synergy. In vivo studies confirmed the efficacy of colistin combined with flavomycin against MDR E. coli infections. This study is the first to demonstrate the synergistic effect between colistin and flavomycin, shedding light on their respective roles in this synergism. Therefore, we propose flavomycin as an adjuvant to enhance the potency of colistin against MDR Gram-negative bacteria. IMPORTANCE: Colistin is a critical antibiotic in combating multi-drug resistant Gram-negative bacteria, but the emergence of mobilized colistin resistance (mcr) undermines its effectiveness. Previous studies have found that colistin can synergy with various drugs; however, its exact mechanisms with hydrophobic drugs are still unrevealed. Generally, the membrane destruction of colistin is thought to be the essential trigger for its interactions with its partner drugs. Here, we use clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) for specifically mutating the binding site of one hydrophobic drug (flavomycin) and show that antimicrobial activity of flavomycin is critical for the synergy. Our results first give the evidence that the synergy is set off by colistin's membrane destruction and operated the final antimicrobial function by its partner drugs.

Synergistic Effects of Capric Acid and Colistin against Colistin-Susceptible and Colistin-Resistant Enterobacterales.

Colistin is a last-line antibiotic against Gram-negative pathogens. However, the emergence of colistin resistance has substantially reduced the clinical effectiveness of colistin. In this study, synergy between colistin and capric acid was examined against twenty-one Gram-negative bacterial isolates (four colistin-susceptible and seventeen colistin-resistant). Checkerboard assays showed a synergistic effect against all colistin-resistant strains [(FICI, fractional inhibitory concentration index) = 0.02-0.38] and two colistin-susceptible strains. Time-kill assays confirmed the combination was synergistic. We suggest that the combination of colistin and capric acid is a promising therapeutic strategy against Gram-negative colistin-resistant strains.

[Construction and Characterization of B850-Only LH2 Energy Transfer System in Purple Bacteria].

To seek microscopic molecular mechanism of energy transfer and complex reconstitution in the photosynthesis, the conditions for construction of B850-only peripheral light-harvesting complex (LH2) and their properties were investigated using absorption, fluorescence spectroscopy, molecular sieve chromatography, ultrafiltration and sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) from the purple bacteria. The results indicated that bacteriochlorophylls (BChl) of B800 incubated in 10 mmo · L(-1) Tris-HCl (pH 8.0) buffer are selectively released from their binding sites of LH2 of Rhodobacter azotoformans (A-LH2) by 0.08% (W/V) SDS. B850-only A-LH2 was constructed after removing free BChl mixing with 10% methyl alcohol by ultrafiltration. B850 BChl was released after A-LH2 was incubated for 240 min in dark at room temperature (RT). While BChl of B800 incubated in pH 1.9 buffer were selectively released from their binding sites of LH2 of Rhodopseudomonas palustris (P-LH2). The authors acquired two components using molecular sieve chromatography. Free BChl of one component was not removed and self-assembled to P-LH2. The other removed free BChl and B850-only P-LH2 was constructed. B850 unchanged after P-LH2 was incubated. P-LH2 α and ß subunits have different molecular weights, but those of A-LH2 are in the contrary. It is concluded that B850-only P-LH2 is more stable than A-LH2. The enigmatic split of the B800 absorption band was not observed in these LH2, but we acquired two kinds of B800-released LH2 from Rhodopseudomonas palustris. The authors' results may provide a new light to separate homogeneous Apoprotein LH2.

A meta-analysis on efficacy of intra-aortic balloon pump therapy in patients with acute myocardial infarction / 中华心血管病杂志

<p><b>OBJECTIVE</b>To analyze the efficacy and safety of intra-aortic balloon pump (IABP) therapy in patients with acute myocardial infarction(AMI) based on the meta-analysis.</p><p><b>METHODS</b>Eligible published randomized controlled clinical research (RCT) were retrieved in the Pubmed, EMBase, Cochrane, China biological medical literature, Wanfang, VIP and CNKI database from 1980 to April 2, 2012. The analysis was performed with the software of RevMan 5.1.</p><p><b>RESULTS</b>Thirteen RCTs with 1958 patients (AMI with IABP therapy, n = 970,without IABP therapy, n = 988) were included. The 30-day mortality between the two groups was similar (RR = 0.77, 95%CI 0.58-1.03, P = 0.08), but the 30-day mortality in the cardiac shock subgroup was significantly lower in IABP group than in without IABP group (RR = 0.65, 95%CI 0.44-0.97, P = 0.04). The 6-month mortality was significantly lower in IABP group than in without IABP group (RR = 0.72, 95%CI 0.55-0.94, P = 0.02). The incidence of major bleeding was significantly higher in IABP group than in without IABP group (RR = 1.43, 95%CI 1.16-1.75, P < 0.01).</p><p><b>CONCLUSION</b>IABP therapy is effective to reduce earlier mortality post AMI, particularly for patients with cardiac shock.</p>