Catheters are indispensable tools of modern medicine, but catheter-associated infection is a significant clinical problem, even when stringent sterile protocols are observed. When the bacteria colonize catheter surfaces, they tend to form biofilms making them hard to treat with conventional antibiotics. Hence, there is a great need for inherently antifouling and antibacterial catheters that prevent bacterial colonization. This paper reports the preparation of nonleachable antibiofilm and antibacterial cationic film coatings directly polymerized from actual tubular silicone catheter surfaces via the technique of supplemental activator and reducing agent surface-initiated atom-transfer radical polymerization (SARA SI-ATRP). Three cross-linked cationic coatings containing (3-acrylamidopropyl) trimethylammonium chloride (AMPTMA) or quaternized polyethylenimine methacrylate (Q-PEI-MA) together with a cross-linker (polyethylene glycol dimethacrylate, PEGDMA) were tested. The in vivo antibacterial and antibiofilm effect of these nonleachable covalently linked coatings (using a mouse catheter model) can be tuned to achieve 1.95 log (98.88%) reduction and 1.26 log (94.51%) reduction of clinically relevant pathogenic bacteria (specifically with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE)). Our good in vivo bactericidal killing results using the murine catheter-associated urinary tract infection (CAUTI) model show that SARA SI-ATRP grafting-from technique is a viable technique for making nonleachable antibiofilm coating even on "small" (0.30/0.64 mm inner/outer diameter) catheter.
Cationic polymers are promising antibacterial agents because bacteria have a low propensity to develop resistance against them, but they usually have low biocompatibility because of their hydrophobic moieties. Herein, we report a new biodegradable and biocompatible chitosan-derived cationic antibacterial polymer, 2,6-diamino chitosan (2,6-DAC). 2,6-DAC shows excellent broad-spectrum antimicrobial activity with minimum inhibitory concentrations (MICs) of 8–32 μg/mL against clinically relevant and multidrug-resistant (MDR) bacteria including Listeria monocytogenes, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Furthermore, 2,6-DAC shows an excellent synergistic effect with various clinically relevant antibiotics proved by decreasing the MICs of the antibiotics against MDR A. baumannii and methicillin-resistant Staphylococcus aureus to <1 μg/mL. In vivo biocompatibility of 2,6-DAC is proved by a dosage of 100 mg/kg compound via oral administration and 25 mg/kg compound via intraperitoneal injection to mice; 2,6-DAC does not cause any weight loss and any significant change in liver and kidney biomarkers or the important blood electrolytes. The combinations of 2,6-DAC together with novobiocin and rifampicin show >2.4 log10 reduction of A. baumannii in murine intraperitoneal and lung infection models. The novel chitosan derivative, 2,6-DAC, can be utilized as a biocompatible broad-spectrum cationic antimicrobial agent alone or in synergistic combination with various antibiotics.
Antibiotic-resistant infections are predicted to kill 10 million people worldwide per year by 2050 and to cost the global economy 100 trillion USD. Novel approaches and alternatives to conventional antibiotics are urgently required to combat antimicrobial resistance. We have synthesized a chitosan-based oligolysine antimicrobial peptide, CSM5-K5 (where CSM denotes chitosan monomer repeat units and K denotes lysine amino acid repeat units), that targets multidrug-resistant (MDR) bacterial species. Here, we show that CSM5-K5 exhibits rapid bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA), MDR Escherichia coli, and vancomycin-resistant Enterococcus faecalis (VRE). Combinatorial therapy of CSM5-K5 with antibiotics to which each organism is otherwise resistant restores sensitivity to the conventional antibiotic. CSM5-K5 alone significantly reduced preformed bacterial biofilm by 2–4 orders of magnitude and, in combination with conventional antibiotics, reduced preformed biofilm by more than 2–3 orders of magnitude at subinhibitory concentrations. Moreover, using a mouse excisional wound infection model, CSM5-K5 treatment reduced bacterial burdens by 1–3 orders of magnitude and acted synergistically with oxacillin, vancomycin, and streptomycin to clear MRSA, VRE, and MDR E. coli, respectively. Importantly, little to no resistance against CSM5-K5 arose for any of the three MDR bacteria during 15 days of serial passage. Furthermore, low level resistance to CSM5-K5 that did arise for MRSA conferred increased susceptibility (collateral sensitivity) to the β-lactam antibiotic oxacillin. This work demonstrates the feasibility and benefits of using this synthetic cationic peptide as an alternative to, or in combination with, traditional antibiotics to treat infections caused by MDR bacteria.
The xnp1 remnant P2-type prophage of Xenorhabdus nematophila produces xenorhabdicin that is active against closely related species. Xenorhabdicin had not been characterized previously in other Xenorhabdus species. Here, we show xenorhabdicin production in six different strains of Xenorhabdus bovienii. The sequenced genome of X. bovienii SS-2004 was found to possess a highly conserved remnant P2-type cluster (xbp1). Inactivation of the xbpS1 sheath gene resulted in loss of bacteriocin activity, indicating that the xbp1 locus was required for xenorhabdicin production. xbp1 and xnp1 contain a CI-type repressor, a dinI gene involved in stabilization of ssDNA-RecA complexes and are inducible with mitomycin C, suggesting that both loci are regulated by cleavage of the CI repressor. Both xnp1 and xbp1 lack typical P2-type lysis genes but contain a predicted endolysin gene (enp) that may be involved in cell lysis. The main tail fibers of xnp1 and xbp1 are mosaic structures with divergent C-terminal regions suggesting they differ in host specificity. Several genes encoding C-terminal tail fiber fragments are present in the same position in xnp1 and xbp1. Recombination between the main fiber genes and the C-terminal fragments could potentially expand the host range specificity of xenorhabdicin in the respective strains.
Sortase A (SrtA) is a membrane-associated enzyme that anchors surface-exposed proteins to the cell wall envelope of Gram-positive bacteria such as Staphylococcus aureus. As SrtA is essential for Gram-positive bacterial pathogenesis but dispensable for microbial growth or viability, SrtA is considered a favorable target for the enhancement of novel anti-infective drugs that aim to interfere with key bacterial virulence mechanisms, such as biofilm formation, without developing drug resistance. Here, we used virtual screening to search an in-house natural compound library and identified two natural compounds, N1287 (Skyrin) and N2576 ((4,5-dichloro-1H-pyrrol-2-yl)-[2,4-dihydroxy-3-(4-methyl-pentyl)-phenyl]-methanone) that inhibited the enzymatic activity of SrtA. These compounds also significantly reduced the growth of S. aureus but possessed moderate mammalian toxicity. Furthermore, S. aureus strains treated with these compounds exhibited reduction in adherence to host fibrinogen, as well as biofilm formation. Hence, these compounds may represent an anti-infective therapy without the side effects of antibiotics.
Peptidoglycan oligomers have been derived from chitosan, using a top-down bio-hybrid strategy, as highly bacteria-specific substrates.
Xenorhabdus species are bacterial symbionts of Steinernema nematodes and pathogens of susceptible insects. Different species of Steinernema nematodes carrying specific species of Xenorhabdus can invade the same insect, thereby setting up competition for nutrients within the insect environment. While Xenorhabdus species produce both diverse antibiotic compounds and prophage-derived R-type bacteriocins (xenorhabdicins), the functions of these molecules during competition in a host are not well understood. Xenorhabdus bovienii (Xb-Sj), the symbiont of Steinernema jollieti, possesses a remnant P2-like phage tail cluster, xbp1, that encodes genes for xenorhabdicin production. We show that inactivation of either tail sheath (xbpS1) or tail fibre (xbpH1) genes eliminated xenorhabdicin production. Preparations of Xb-Sj xenorhabdicin displayed a narrow spectrum of activity towards other Xenorhabdus and Photorhabdus species. One species, Xenorhabdus szentirmaii (Xsz-Sr), was highly sensitive to Xb-Sj xenorhabdicin but did not produce xenorhabdicin that was active against Xb-Sj. Instead, Xsz-Sr produced high-level antibiotic activity against Xb-Sj when grown in complex medium and lower levels when grown in defined medium (Grace’s medium). Conversely, Xb-Sj did not produce detectable levels of antibiotic activity against Xsz-Sr. To study the relative contributions of Xb-Sj xenorhabdicin and Xsz-Sr antibiotics in interspecies competition in which the respective Xenorhabdus species produce antagonistic activities against each other, we co-inoculated cultures with both Xenorhabdus species. In both types of media Xsz-Sr outcompeted Xb-Sj, suggesting that antibiotics produced by Xsz-Sr determined the outcome of the competition. In contrast, Xb-Sj outcompeted Xsz-Sr in competitions performed by co-injection in the insect Manduca sexta, while in competition with the xenorhabdicin-deficient strain (Xb-Sj:S1), Xsz-Sr was dominant. Thus, xenorhabdicin was required for Xb-Sj to outcompete Xsz-Sr in a natural host environment. These results highlight the importance of studying the role of antagonistic compounds under natural biological conditions.
13Antibiotic-resistant infections are predicted to kill 10 million people worldwide per year 14 by 2050 and to cost the global economy 100 trillion USD. Novel approaches and 15 alternatives to conventional antibiotics are urgently required to combat antimicrobial 16 resistance. We have synthesized a chitosan-based oligolysine antimicrobial peptide, 17 CSM5-K5, which targets multidrug resistant (MDR) bacterial species. Here we show 18 that CSM5-K5 exhibits rapid bactericidal activity against methicillin resistant 19 Staphylococcus aureus (MRSA), MDR Escherichia coli, and vancomycin resistant 20 Enterococcus faecalis (VRE). Combinatorial therapy of CSM5-K5 with antibiotics to 21 which each organism is otherwise resistant restores sensitivity to the conventional 22 antibiotic. CSM5-K5 alone significantly reduced pre-formed bacterial biofilm by two-four 23 orders of magnitude and, in combination with traditional antibiotics, reduced pre-formed 24 biofilm by more than two-three orders of magnitude at sub inhibitory concentrations. 25Moreover, using a mouse excisional wound infection model, CSM5-K5 treatment 26 reduced bacterial burdens by one to three orders of magnitude, and acted 27 synergistically with vancomycin and tetracycline to clear VRE and MDR E. coli, 28 respectively. Importantly, little to no resistance against CSM5-K5 arose for any of the 29 three MDR bacteria during 15 days of serial passage. This work demonstrates the 30 feasibility and benefits of using this synthetic cationic peptide as alternative to, or in 31 combination with, traditional antibiotics to treat infections caused by MDR bacteria. 32 33Antibiotic resistance is a threat to global public health and sustainability (1). Antibiotic 35 resistance currently accounts for an estimated 70,000 annual deaths globally, and in the 36 absence of new therapeutics, infections caused by resistant "superbugs" could kill an 37 additional 10 million people each year worldwide by 2050, surpassing cancer (2). 38 Moreover, by 2050, antibiotic resistant infections are estimated to cost up to 3.5% of the 39 global GDP, equivalent to 100 trillion USD (2). Because corporate antibiotic 40 development pipelines of have progressively declined over the past 20 years (3), there 41 is substantial interest in seeking alternative therapeutic approaches to combat these 42 multidrug resistant (MDR) pathogens. 43 44 Host-derived antimicrobial peptides (CAMPs), typically composed of cationic and 45 hydrophobic domains, have garnered interest as alternative therapies for MDR 46 infections. CAMPs are electrostatically attracted to anionic bacterial cell surfaces, 47followed by peptide insertion into the lipid bilayer via their hydrophobic residues (4, 5). 48Chitosan is a polysaccharide composed of repeating N-glucosamine, with a structure 49 similar to that of bacterial peptidoglycan. This unique feature of chitosan renders it 50 potentially compatible with the bacterial cell wall. Numerous studies have examined the 51 efficacy of chitosan-CAMP hybrids containing quaterna...
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