Designer broad-spectrum polyimidazolium antibiotics

For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.

AMPs and AMP mimics have attracted considerable attention as candidates for therapeutic development (1). The basic design elements include a region of charged residues, generally cationic residues, enabling interaction with bacterial cell surfaces, combined with a hydrophobic nature in AMPs (2). Unfortunately, AMPs and related polymers, in general, have one or more issues that limit their use as broad-spectrum antibiotics. Some are quite toxic to human cells, the potency of some is not adequate for human administration, others are sensitive to salt at levels present in human fluids, and some are too difficult and expensive to synthesize (3, 4). One broad-spectrum antimicrobial peptide, CST has seen increased recent use as a last resort antibiotic. CST is believed to kill bacteria by virtue of its ability to disrupt membrane integrity (5). This antibiotic requires intravenous administration and is nephrotoxic (6). The emergence of CST-resistant pathogens has also become a significant problem (7). We are unaware of any new broad-spectrum AMPs that have advanced to clinical trials.Imidazolium (IM) salts are antimicrobials (8), and there is an emerging literature on antimicrobial activity of side-chain and main-chain polyimidazolium (PIM) salts with chemical structures that are in some ways similar to those we describe. Although PIMs are potent antimicrobials, there are biocompatibility problems hindering their development, and some have somewhat limited activity spectra. As with other AMPs, there have been toxicity issues, potency issues, and delivery issues as many have large molecular masses, and there is little known about mammalian cell toxicity or mechanism of action (9–12).Here we show that members of a series of PIMs we designed and synthesized are potent broad-spectrum antibacterial compounds. We selected two for further analysis and showed they retain activity even against pan-antibiotic-resistant bacteria. Unlike CST and many other AMPs, which disrupt bacterial membranes, our model PIM is bactericidal without disrupting bacterial membranes. Our experiments provide insights about mechanism of action, the potential for the emergence of PIM resistance, and indicate PIMs are effective against a model gram-negative and a model gram-positive pathogen in murine infection models.     

Effect of photobiomodulation therapies on the root resorption associated with orthodontic forces: a pilot study using micro computed tomography

Clinical Oral Investigations - The aim of this study is to investigate the effect of photobiomodulation therapies on root resorption compared with the placebo group. Thirty patients who were...     

Corrosive Substance Ingestion in Children

Objectives

To evaluate children who ingested corrosive substances, in terms of demographic features, nature of ingested substances, clinical findings, management and complications.

Methods

A total of 1709 cases aged between 0 and 16 y who ingested corrosive substance were analyzed retrospectively by evaluating the medical records of the patients.

Results

The mean age of the cases was 35.23?±?30.65 mo and male:female ratio was 1.45. Forty one percent of corrosive substances causing intoxication contained NaOH. Thirty percent of the families consisted of 5 or more members. Fourteen percent of the mothers were illiterate. Stricture formation was observed in 29 (1.69 %) of the cases during follow-up. In 79.31 % of those cases alkaline substance ingestion was responsible for stricture development. It was found that stricture formation occurred more frequently among cases who were older than 5 y of age and this finding was statistically significant (p?=?0.001).

Conclusions

The cases older than 5 y of age with the diagnosis of grade 2b esophagitis must be followed up closely for the stricture formation. In order to protect children from corrosive ingestion, importance must be given to preventive measures such as education of families, keeping and storing these agents out of the reach of children and providing safety caps for these products.     

The evaluation of MTA and Biodentine as a pulpotomy materials for carious exposures in primary teeth

Clinical Oral Investigations - This study examined the effects of MTA and Biodentine on the clinical and radiographic success rates of pulpotomies performed on primary teeth with carious pulp...     

Prognostic value of cutaneous reinnervation with GAP-43 in oxaliplatin-induced neuropathy

Journal of Neurology - Oxaliplatin-induced neuropathy (OIN) implies axonal damage of both small and large sensory nerve fibers. We aimed at comparing the neurophysiological changes occurred after...     

Association of cholesterol 7α-hydroxylase (CYP7A1) promoter polymorphism (rs3808607) and cholesterol 24S-hydroxylase (CYP46A1) intron 2 polymorphism (rs754203) with serum lipids,vitamin D levels,and multiple sclerosis risk in the Turkish population

Neurological Sciences - Patients with multiple sclerosis (MS) have significantly lower vitamin D levels. Cholesterol is known to be the precursor for vitamin D synthesis, and cholesterol removal is...