Amine Basicity of Quinoline ATP Synthase Inhibitors Drives Antibacterial Activity against .

(PA), a Gram-negative pathogen, is a common cause of nosocomial infections, especially in immunocompromised and cystic fibrosis patients. PA is intrinsically resistant to many currently prescribed antibiotics due to its tightly packed, anionic lipopolysaccharide outer membrane, efflux pumps, and ability to form biofilms. PA can acquire additional resistance through mutation and horizontal gene transfer.

Quinoline Compounds Targeting the -Ring of ATP Synthase Inhibit Drug-Resistant .

(PA) is a Gram-negative, biofilm-forming bacterium and an opportunistic pathogen. The growing drug resistance of PA is a serious threat that necessitates the discovery of novel antibiotics, ideally with previously underexplored mechanisms of action. Due to their central role in cell metabolism, bacterial bioenergetic processes are of increasing interest as drug targets, especially with the success of the ATP synthase inhibitor bedaquiline to treat drug-resistant tuberculosis.

Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents against Pseudomonas aeruginosa.

Due to the global rise in the number of antibiotic resistant bacterial infections over the past 20 years, there is a dire need for the development of small molecule antibiotics capable of overcoming resistance mechanisms in pathogenic bacteria. Antibiotic development against Gram-negative pathogens, such as Pseudomonas aeruginosa, is especially challenging due to their additional outer membrane which reduces antibiotic entry. Recently, it has been shown that a broad range of nitrogen functionality, including guanidines, amidines, primary amines, imidazolines, and imidazoles, promote antibiotic and adjuvant activity in Gram-negative bacteria, but few of these have been targeted towards Pseudomonas aeruginosa specifically despite this pathogen being deemed a critical threat by the United States Centers for Disease Control and Prevention.

Generating Publishable Data from Course-Based Undergraduate Research Experiences in Chemistry.

Embedding Course-based Undergraduate Research Experiences (CUREs) into chemistry curricula has become a best practice due to the overwhelming evidence that these experiences deepen students' content comprehension, improve students' problem-solving skills, and increase retention within the major. For these reasons, faculty are often encouraged to develop CUREs for their courses, which typically take a substantial amount of effort and administrative/financial support. To justify these efforts, one of the most cited benefits of CURE development for faculty specifically is that they can pilot research projects and publish data produced during CUREs in scientific publications.

Integration of Antimicrobials and Delivery Systems: Synergistic Antibiofilm Activity with Biodegradable Nanoemulsions Incorporating Pseudopyronine Analogs.

Multi-drug-resistant (MDR) bacteria, including methicillin-resistant (MRSA), pose a significant challenge in healthcare settings. Small molecule antimicrobials (SMAs) such as α-pyrones have shown promise as alternative treatments for MDR infections. However, the hydrophobic nature of many SMAs limits their solubility and efficacy in complex biological environments.

Design and evaluation of poly-nitrogenous adjuvants capable of potentiating antibiotics in Gram-negative bacteria.

Antibiotic resistance has been a growing public health crisis since the 1980s. Therefore, it is essential not only to continue to develop novel antibiotics but also to develop new methods for overcoming resistance mechanisms in pathogenic bacteria so antibiotics can be reactivated towards these resistant strains. One common cause of antibiotic resistance in Gram-negative bacteria is reduced permeability of the tightly packed, negatively charged lipopolysaccharide outer membrane (OM), which dramatically reduces or even prevents antibiotic accumulation within the cell.

Total synthesis and antibacterial evaluation of Empetroxepins A and B and related analogs.

Empetroxepins A and B, which are 10,11-dihydrodibenz[b,f]oxepins produced by the Black Crowberry (Empetrum nigrum), displayed weak anti-tubercular activity upon isolation, but have not been explored for antibiotic activity despite their molecular similarity to other phenolic antibacterial natural products. Herein we detail the first total synthesis of Empetroxepins A and B via a selective demethylation strategy and antibacterial structure activity relationship (SAR) study of the natural products and related analogs. Empetroxepin A was found to be weakly active against susceptible strains of Staphylococcus aureus (SA) and Bacillus subtilis (BS) with a minimum inhibitory concentration (MIC) of 256 μg/mL against both bacteria, whereas Empetroxepin B was found to be weakly active against only BS (MIC = 256 μg/mL).

Synthesis and Evaluation of ATP Synthase Inhibitors.

New antibiotics with unique biological targets are desperately needed to combat the growing number of resistant bacterial pathogens. ATP synthase, a critical protein found in all life, has recently become a target of interest for antibiotic development due to the success of the anti-tuberculosis drug bedaquiline, and while many groups have worked on developing drugs to target bacterial ATP synthase, few have been successful at inhibiting (PA) ATP synthase specifically. PA is one of the leading causes of resistant nosocomial infections across the world and is extremely challenging to treat due to its various antibiotic resistance mechanisms for most commonly used antibiotics.

Advances in antibiotic drug discovery: reducing the barriers for antibiotic development.

Antibiotic drug discovery has been an essential field of research since the early 1900s, but the threat from infectious bacteria has only increased over the decades because of the emergence of widespread multidrug resistance. In this review, we discuss the recent advances in natural product, computational and medicinal chemistry that have reinvigorated the field of antibiotic drug discovery while giving perspective on how easily, both in cost and in expertise, these methods can be implemented by other researchers with the goal of increasing the number of scientists contributing to this public health crisis.

Short chain α-pyrones capable of potentiating penicillin G against Pseudomonas aeruginosa.

The dramatic increase in bacterial resistance over the past three decades has greatly reduced the effectiveness of nearly all clinical antibiotics, bringing infectious disease to the forefront as a dire threat to global health. To combat these infections, adjuvant therapies have emerged as a way to reactivate known antibiotics against resistant pathogens. Herein, we report the evaluation of simplified α-pyrone adjuvants capable of potentiating penicillin G against Pseudomonas aeruginosa, a Gram-negative pathogen whose multidrug-resistant strains have been labeled by the Centers for Disease Control and Prevention as a serious threat to public health.

Development of a Robust and Quantitative High-Throughput Screening Method for Antibiotic Production in Bacterial Libraries.

Over the past 30 years, there has been a dramatic rise in the number of infections caused by multidrug-resistant bacteria, which have proliferated due to the misuse and overuse of antibiotics. Over this same time period, however, there has also been a decline in the number of antibiotics with novel mechanisms of action coming to market. Therefore, there is a growing need for an increase in the speed at which new antibiotics are discovered and developed.

Isolation of the antibiotic pseudopyronine B and SAR evaluation of C3/C6 alkyl analogs.

Natural products are an abundant source of structurally diverse compounds with antibacterial activity that can be used to develop new and potent antibiotics. One such class of natural products is the pseudopyronines. Here we present the isolation of pseudopyronine B (2) from a Pseudomonas species found in garden soil in Western North Carolina, and SAR evaluation of C3 and C6 alkyl analogs of the natural product for antibacterial activity against Gram-positive and Gram-negative bacteria.

A fundamental relationship between hydrophobic properties and biological activity for the duocarmycin class of DNA-alkylating antitumor drugs: hydrophobic-binding-driven bonding.

Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA that feature the incorporation of ethylene glycol units (n = 1-5) into the methoxy substituents of the trimethoxyindole subunit are described. These derivatives exhibit progressively increasing water solubility along with progressive decreases in cell growth inhibitory activity and DNA alkylation efficiency with the incremental ethylene glycol unit incorporations. Linear relationships of cLogP with -log IC50 for cell growth inhibition and -log AE (AE = cell-free DNA alkylation efficiency) were observed, with the cLogP values spanning the productive range of 2.

Evaluation of a reductively activated duocarmycin prodrug against murine and human solid cancers.

In treating cancer with clinically approved chemotherapies, the high systemic toxicity and lack of selectivity for malignant cells often result in an overall poor response rate. One pharmacological approach to improve patient response is to design targeted therapies that exploit the cancer milieu by reductively activating prodrugs, which results in the selective release of the free drug in the tumor tissue. Previously, we characterized prodrugs of seco-CBI-indole 2 (CBI-indole 2) designed to be activated in hypoxic tumor microenvironments, wherein the tumor maintains higher concentrations of "reducing" nucleophiles capable of preferentially releasing the free drug by nucleophilic attack on a weak N-O bond.

Efficacious cyclic N-acyl O-amino phenol duocarmycin prodrugs.

Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6/10 one year survivors), substantially exceeding that of the free drug, that its therapeutic window of activity is much larger, permitting a dosing ≥ 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold).

Total synthesis of kopsinine.

The use of a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of an 1,3,4-oxadiazole in the divergent total synthesis of kopsinine (1), featuring an additional unique SmI(2)-promoted transannular cyclization reaction for formation of the bicyclo[2.2.2]octane central to its hexacyclic ring system, is detailed.

A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct.

A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug.

Synthesis and antibiofilm activity of a second-generation reverse-amide oroidin library: a structure-activity relationship study.

A second-generation library of 2-aminoimidazole-based derivatives incorporating a "reversed amide" (RA) motif in comparison to the marine natural product oroidin were synthesized and subsequently assayed for antibiofilm activity against the medically relevant Gram-negative proteobacteria P. aeruginosa and A. baumannii.