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Title
Abstract
Figures
Introduction
Mass Spectrometry and Amino Acid Analysis
Stereochemical Analysis
Results
Discussion
References
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Biology
Microbiology

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https://doi.org/10.3389/FMICB.2018.02864.S001
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Abstract
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Nosocomial infections caused by antibiotic-resistant Gram-negative pathogens are a significant concern, prompting the need for safer polymyxin therapies. In this study, two antimicrobial compounds, P1 and P2, were isolated from Paenibacillus dendritiformis strain PV3-16 and identified as polymyxin A2 and A1. Both compounds showed comparable efficacy to standard polymyxins against MDR clinical isolates, with P1 demonstrating superior activity and lower toxicity to immune cells. This study represents the first comprehensive evaluation of polymyxin A, suggesting P1 as a promising candidate for further development as a therapeutic agent.

Figures (11)
FIGURE 2 | Amino acid analysis of P2 (A) and polymyxin B (B). FIGURE 3 | Stereochemical analysis of P2 using Marfey’s reagent. (A) Control Marfey’s reagent (B) Standard L-Dab (C) Standard D,L-Dab mixture (D) P2 hydrolysate. The ratio of L-Dab to D-Dab was approximately 5:1 in P2. This suggests that there is one D-Dab in the compound.
FIGURE 2 | Amino acid analysis of P2 (A) and polymyxin B (B). FIGURE 3 | Stereochemical analysis of P2 using Marfey’s reagent. (A) Control Marfey’s reagent (B) Standard L-Dab (C) Standard D,L-Dab mixture (D) P2 hydrolysate. The ratio of L-Dab to D-Dab was approximately 5:1 in P2. This suggests that there is one D-Dab in the compound.
PB, Polymyxin B; PE, Polymyxin. TABLE 1 | MIC data of P1 and P2 against quality control strains.
PB, Polymyxin B; PE, Polymyxin. TABLE 1 | MIC data of P1 and P2 against quality control strains.
FIGURE 4 | Proposed 2D structure of P1 and P2. RESULTS
FIGURE 4 | Proposed 2D structure of P1 and P2. RESULTS
TABLE 2 | MIC of isolated compounds in MDR clinical isolates.
TABLE 2 | MIC of isolated compounds in MDR clinical isolates.
FIGURE 5 | Time-kill kinetics of P1 and P2 against (A) E. coli ATCC 25922 and (B) P. aeruginosa ATCC 27853. The experiment was carried out in triplicate and two biological repeats were performed. Data plotted as mean + SD. PB, Polymyxin B; PE, Polymyxin. The bold values highlights the lower MIC of the compound P7 than the standard polymyxins.
FIGURE 5 | Time-kill kinetics of P1 and P2 against (A) E. coli ATCC 25922 and (B) P. aeruginosa ATCC 27853. The experiment was carried out in triplicate and two biological repeats were performed. Data plotted as mean + SD. PB, Polymyxin B; PE, Polymyxin. The bold values highlights the lower MIC of the compound P7 than the standard polymyxins.
FIGURE 7 | Membrane permeabilization assays with E. coli ATCC 25922. (A) NPN uptake assay to check the outer membrane permeabilization. (B) Inner membrane permeabilization using fluorescent dyes SYTO9 and PI; the concentration of each compound is 10 g/ml. Control in (B) is cells without peptide treatment. Data is plotted as Mean + SD of three replicates. Two biological repeats were performed. reported which differ in N-terminal fatty acid chain length. The major components of polymyxin B and E are B, and Bp, and E, and E) respectively. B; and E; contain 6-methyloctanoic acid while other two contain isooctanoic acid (i.e., 6-methylheptanoic acid) making a difference of 14 Da (Storm et al., 1977; Cui et al. 2018). We believed that our compounds Pl and P2 Table 1 shows the MICs of P1 and P2 compounds along with reference polymyxin B and E against a wide panel of quality control strains. All compounds showed excellent activity against
FIGURE 7 | Membrane permeabilization assays with E. coli ATCC 25922. (A) NPN uptake assay to check the outer membrane permeabilization. (B) Inner membrane permeabilization using fluorescent dyes SYTO9 and PI; the concentration of each compound is 10 g/ml. Control in (B) is cells without peptide treatment. Data is plotted as Mean + SD of three replicates. Two biological repeats were performed. reported which differ in N-terminal fatty acid chain length. The major components of polymyxin B and E are B, and Bp, and E, and E) respectively. B; and E; contain 6-methyloctanoic acid while other two contain isooctanoic acid (i.e., 6-methylheptanoic acid) making a difference of 14 Da (Storm et al., 1977; Cui et al. 2018). We believed that our compounds Pl and P2 Table 1 shows the MICs of P1 and P2 compounds along with reference polymyxin B and E against a wide panel of quality control strains. All compounds showed excellent activity against
FIGURE 6 | Scanning electron microscopy. Upper panel shows control cells without treatment (1) K. pneumoniae BAA-1706, (2) A. baumannii ATCC 19606 and (3) PR aeruginosa ATCC 27853. P1 and P2 were used at a concentration of 10 g/ml at 37°C. The optimized treatment time was 45 min for K. pneumoniae and A. baumanii while PR. aeruginosa was incubated for 2 h. (1a,2a,3a) are cells treated with P1, and (1b,2b,3b) show the cells treated ant DO
FIGURE 6 | Scanning electron microscopy. Upper panel shows control cells without treatment (1) K. pneumoniae BAA-1706, (2) A. baumannii ATCC 19606 and (3) PR aeruginosa ATCC 27853. P1 and P2 were used at a concentration of 10 g/ml at 37°C. The optimized treatment time was 45 min for K. pneumoniae and A. baumanii while PR. aeruginosa was incubated for 2 h. (1a,2a,3a) are cells treated with P1, and (1b,2b,3b) show the cells treated ant DO
FIGURE 8 | Binding isotherms of P1 (A), P2 (B), polymyxin B (C), and polymyxin E (D) with lipopolysaccharide. LPS concentration was 0.05 mM where all fou compounds were used at 1 mg/ml (0.83-0.87 mM). Dissociation constant (Kd) determined as: P1 = 9.52E-07, P2 = 2.94E-06, Polymyxin B = 3.39E-06 and Polymyxin E = 7.04E-06.
FIGURE 8 | Binding isotherms of P1 (A), P2 (B), polymyxin B (C), and polymyxin E (D) with lipopolysaccharide. LPS concentration was 0.05 mM where all fou compounds were used at 1 mg/ml (0.83-0.87 mM). Dissociation constant (Kd) determined as: P1 = 9.52E-07, P2 = 2.94E-06, Polymyxin B = 3.39E-06 and Polymyxin E = 7.04E-06.
FIGURE 9 | Cytotoxicity of Ptand P2 at various concentrations against THP-1 cell line (top) and HEK298 cell line (bottom). PE, polymyxin E and PB, polymyxin B. The experiment was performed in triplicate and is representative of two biological repeats. Data plotted as Mean + SD.
FIGURE 9 | Cytotoxicity of Ptand P2 at various concentrations against THP-1 cell line (top) and HEK298 cell line (bottom). PE, polymyxin E and PB, polymyxin B. The experiment was performed in triplicate and is representative of two biological repeats. Data plotted as Mean + SD.

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