Synthesis of Guanidinium Functionalized Polycarbodiimides and Their Antibacterial Activities

A family of guanidinium-side-chain functionalized polycarbodiimides has been synthesized by allowing an azido guanidinium salt to react with alkyne polycarbodiimides via the copper catalyzed [3 + 2] cycloaddition (Click) reaction. <b>Poly-2</b>(<b>a</b>–<b>d</b>) are cationic/amphiphilic polymers in which the global hydrophilic/hydrophobic balance has been tailored by local alteration of the length of alkyl side chain in the repeat unit of polymers prior to polymerization. The shorter alkyl chains yield water-soluble polymers, <b>Poly</b>-<b>2c</b>, -<b>2d</b>, and -<b>2e</b>. Antibacterial activities of these cationic polycarbodiimides have been investigated for Gram-positive and Gram-negative bacteria that include Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Acinetobacter baumannii. It was observed that the influence of hydrophobic–hydrophilic balance per repeat unit of these polymers have profound effects for both antimicrobial and hemolytic activities. In addition, these polycarbodiimide-guanidinium-triazole conjugates offered moderate to significant antibacterial activity and rapid interaction with red blood cells causing blood precipitation without significant hemolysis in case of <b>Poly</b>-<b>2</b>(<b>b</b>–<b>e</b>). This latter property has the potential to be exploited in the polymer coatings or wound protection

Small Molecule Suppression of Carbapenem Resistance in NDM-1 Producing <i>Klebsiella pneumoniae</i>

The already considerable global public health threat of multidrug-resistant Gram-negative bacteria has become even more of a concern following the emergence of New Delhi metallo-β-lactamase (NDM-1) producing strains of <i>Klebsiella pneumoniae</i> and other Gram-negative bacteria. As an alternative approach to the traditional development of new bactericidal entities, we have identified a 2-aminoimidazole-derived small molecule that acts as an antibiotic adjuvant and is able to suppress resistance of a NDM-1 producing strain of <i>K. pneumoniae</i> to imipenem and meropenem, in addition to suppressing resistance of other β-lactam nonsusceptible <i>K. pneumoniae</i> strains. The small molecule is able to lower carbapenem minimum inhibitory concentrations by up to 16-fold, while exhibiting little bactericidal activity itself

Meridianin D Analogues Display Antibiofilm Activity against MRSA and Increase Colistin Efficacy in Gram-Negative Bacteria

In the last 30 years, development of new classes of antibiotics has slowed, increasing the necessity for new options to treat multidrug resistant bacterial infections. Development of antibiotic adjuvants that increase the effectiveness of currently available antibiotics is a promising alternative approach to classical antibiotic development. Reports of the ability of the natural product meridianin D to modulate bacterial behavior have been rare. Herein, we describe the ability of meridianin D to inhibit biofilm formation of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and to increase the potency of colistin against colistin-resistant and sensitive Gram-negative bacteria. Analogues were identified that are capable of inhibiting and dispersing MRSA biofilms and lowering the colistin MIC to below the CLSI breakpoint against <i>Acinetobacter baumannii</i>, <i>Klebsiella pneumoniae</i>, and <i>Escherichia coli</i>

Probing the Mechanism of LAL-32, a Gold Nanoparticle-Based Antibiotic Discovered through Small Molecule Variable Ligand Display

The unrelenting rise of antimicrobial-resistant bacteria has necessitated the search for novel antibiotic solutions. Herein we describe further mechanistic studies on a 2.0-nm-diameter gold nanoparticle-based antibiotic (designated LAL-32). This antibiotic exhibits bactericidal activity against the Gram-negative bacterium Escherichia coli at 1.0 μM, a concentration significantly lower than several clinically available antibiotics (such as ampicillin and gentamicin), and acute treatment with LAL-32 does not give rise to spontaneous resistant mutants. LAL-32 treatment inhibits cellular division, daughter cell separation, and twin-arginine translocation (Tat) pathway dependent shuttling of proteins to the periplasm. Furthermore, we have found that the <i>cedA</i> gene imparts increased resistance to LAL-32, and shown that an E. coli <i>cedA</i> transposon mutant exhibits increased susceptibility to LAL-32. Taken together, these studies further implicate cell division pathways as the target for this nanoparticle-based antibiotic and demonstrate that there may be inherently higher barriers for resistance evolution against nanoscale antibiotics in comparison to their small molecule counterparts

Small-Molecule Suppression of β‑Lactam Resistance in Multidrug-Resistant Gram-Negative Pathogens

Recent efforts toward combating antibiotic resistance in bacteria have focused on Gram-positive bacteria; however, multidrug-resistant Gram-negative bacteria pose a significant risk to public health. An orthogonal approach to the development of new antibiotics is to develop adjuvant compounds that enhance the susceptibility of drug-resistant strains of bacteria to currently approved antibiotics. This paper describes the synthesis and biological activity of a library of aryl amide 2-aminoimidazoles based on a lead structure from an initial screen. A small molecule was identified from this library that is capable of lowering the minimum inhibitory concentration of β-lactam antibiotics by up to 64-fold

Small Molecule Downregulation of PmrAB Reverses Lipid A Modification and Breaks Colistin Resistance

Infections caused by multi-drug resistant bacteria, particularly Gram-negative bacteria, are an ever-increasing problem. While the development of new antibiotics remains one option in the fight against bacteria that have become resistant to currently available antibiotics, an attractive alternative is the development of adjuvant therapeutics that restore the efficacy of existing antibiotics. We report a small molecule adjuvant that suppresses colistin resistance in multidrug resistant <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i> by interfering with the expression of a two-component system. The compound downregulates the <i>pmrCAB</i> operon and reverses phosphoethanolamine modification of lipid A responsible for colistin resistance. Furthermore, colistin-susceptible and colistin-resistant bacteria do not evolve resistance to combination treatment. This represents the first definitive example of a compound that breaks antibiotic resistance by directly modulating two-component system activity

1,2,4-Triazolidine-3-thiones as Narrow Spectrum Antibiotics against Multidrug-Resistant <i>Acinetobacter baumannii</i>

With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4-triazolidine-3-thiones as narrow spectrum antibiotics. Optimization of the 1,2,4-triazolidine-3-thione scaffold identified a small molecule with potent antibiotic activity against multiple strains of multidrug-resistant and extensively drug-resistant <i>Acinetobacter baumannii</i>. This small molecule also shows single dose, <i>in vivo</i> activity in a <i>Galleria mellonella</i> infection model with <i>A. baumannii</i> and represents a promising start in the development of a class of drugs that can target this bacterial pathogen

Advanced Glycation End Products as a Potential Target for Restructuring the Ovarian Cancer Microenvironment: A Pilot Study

Ovarian cancer is the sixth leading cause of cancer-related death in women, and both occurrence and mortality are increased in women over the age of 60. There are documented age-related changes in the ovarian cancer microenvironment that have been shown to create a permissive metastatic niche, including the formation of advanced glycation end products, or AGEs, that form crosslinks between collagen molecules. Small molecules that disrupt AGEs, known as AGE breakers, have been examined in other diseases, but their efficacy in ovarian cancer has not been evaluated. The goal of this pilot study is to target age-related changes in the tumor microenvironment with the long-term aim of improving response to therapy in older patients. Here, we show that AGE breakers have the potential to change the omental collagen structure and modulate the peritoneal immune landscape, suggesting a potential use for AGE breakers in the treatment of ovarian cancer.</p

Identification of BfmR, a Response Regulator Involved in Biofilm Development, as a Target for a 2‑Aminoimidazole-Based Antibiofilm Agent

2-Aminoimidazoles (2AIs) have been documented to disrupt bacterial protection mechanisms, including biofilm formation and genetically encoded antibiotic resistance traits. Using <i>Acinetobacter baumannii</i>, we provide initial insight into the mechanism of action of a 2AI-based antibiofilm agent. Confocal microscopy confirmed that the 2AI is cell permeable, while pull-down assays identified BfmR, a response regulator that is the master controller of biofilm formation, as a target for this compound. Binding assays demonstrated specificity of the 2AI for response regulators, while computational docking provided models for 2AI–BfmR interactions. The 2AI compound studied here represents a unique small molecule scaffold that targets bacterial response regulators

2B8 potentiates mycobactericidal activity of ß-lactams.

<p>Bactericidal activity of ß-lactams against <i>M</i>. <i>tuberculosis</i> H37Rv was significantly increased after 5 days of treatment in combination with 2B8 or clavulanate compared to when ß-lactams were used alone. Statistical significance was determined comparing each group with ß-lactams only group. *p<0.05, **p<0.01, ***p<0.001 by ANOVA. Experiments were carried out three separate times in duplicate and all results were pooled together for statistical analysis.</p