Promiscuous Pseudomonas: Uptake of Non-Endogenous Ligands for Iron Acquisition.

Iron is an essential nutrient to nearly all living beings. However, its acquisition poses a significant challenge to many organisms, including most bacteria. One of the main iron uptake strategies employed by bacteria is the uptake of siderophores, small molecules that chelate extracellular iron. The pathogenic species Pseudomonas aeruginosa produces two different siderophores, pyochelin and pyoverdine. P. aeruginosa senses the amount of bioavailable extracellular iron in order to regulate the production levels of each of these two siderophores. In previous work, we found that a series of pyochelin biosynthetic shunt products enhanced the growth of P. aeruginosa in iron-depleted conditions when prechelated with iron. Thus, on the basis of these results, we investigated the physiochemical and biological properties of a series of non-native oxygen counterparts to these metabolites in the current study.

An Efficient Synthesis of 3-Alkylpyridine Alkaloids Enables Their Biological Evaluation.

3-Alkylpyridine alkaloids (3-APAs) isolated from the arctic sponge Haliclona viscosa are a promising group of bioactive marine alkaloids. However, due to limited bioavailability, investigations of their bioactivity have been hampered. Additionally, synthesis of a common intermediate requires the use of protecting groups and harsh conditions. In this work, we developed a simple and concise two-step route to nine different natural and synthetic haliclocyclins. These compounds displayed modest antibiotic activity against several Gram-positive bacterial strains.

Pyochelin Biosynthetic Metabolites Bind Iron and Promote Growth in Pseudomonads Demonstrating Siderophore-like Activity.

Pseudomonads employ several strategies to sequester iron vital for their survival including the use of siderophores such as pyoverdine and pyochelin. Similar in structure but significantly less studied are pyochelin biosynthetic byproducts, dihydroaeruginoic acid, aeruginoic acid, aeruginaldehyde (IQS), and aeruginol, along with two other structurally related molecules, aerugine and pyonitrins A-D, which have all been isolated from numerous Pseudomonad extracts. Because of the analogous substructure of these compounds to pyochelin, we hypothesized that they may play a role in iron homeostasis or have a biological effect on other bacterial species. Herein, we discuss the physiochemical evaluation of these molecules and disclose, for the first time, their ability to bind iron and promote growth in Pseudomonads.

Building trans-bicyclo[4.4.0]decanes/decenes in complex multifunctional frameworks: the case for antibiotic development.

Covering: 2000 to 2020. trans-Bicyclo[4.4.0]decane/decene (such as trans-decalin and trans-octalin)-containing natural products display a wide range of structural diversity and frequently exhibit potent and selective antibacterial activities. With one of the major factors in combatting antibiotic resistance being the discovery of novel scaffolds, the efficient construction of these natural products is an attractive pursuit in the development of novel antibiotics. This highlight aims to provide a critical analysis on how the presence of dense architectural and stereochemical complexity necessitated special strategies in the synthetic pursuits of these natural trans-bicyclo[4.4.0]decane/decene antibiotics.

Target-Based Design of Promysalin Analogues Identifies a New Putative Binding Cleft in Succinate Dehydrogenase.

Promysalin is a small-molecule natural product that specifically inhibits growth of the Gram-negative pathogen Pseudomonas aeruginosa (PA). This activity holds promise in the treatment of multidrug resistant infections found in immunocompromised patients with chronic illnesses, such as cystic fibrosis. In 2015, our lab completed the first total synthesis; subsequent analogue design and SAR investigation enabled identification of succinate dehydrogenase (Sdh) as the biological target in PA. Herein, we report the target-guided design of new promysalin analogues with varying alkyl chains, one of which is on par with our most potent analogue to date. Computational docking revealed that some analogues have a different orientation in the Sdh binding pocket, placing the terminal carbon proximal to a tryptophan residue. This inspired the design of an extended side chain analogue bearing a terminal phenyl moiety, providing a basis for the design of future analogues.

Opioid overdose deaths and potentially inappropriate opioid prescribing practices (PIP): A spatial epidemiological study.

INTRODUCTION: Opioid overdose deaths quintupled in Massachusetts between 2000 and 2016. Potentially inappropriate opioid prescribing practices (PIP) are associated with increases in overdoses. The purpose of this study was to conduct spatial epidemiological analyses of novel comprehensively linked data to identify overdose and PIP hotspots. METHODS: Sixteen administrative datasets, including prescription monitoring, medical claims, vital statistics, and medical examiner data, covering >98% of Massachusetts residents between 2011-2015, were linked in 2017 to better investigate the opioid epidemic. PIP was defined by six measures: ≥100 morphine milligram equivalents (MMEs), co-prescription of benzodiazepines and opioids, cash purchases of opioid prescriptions, opioid prescriptions without a recorded pain diagnosis, and opioid prescriptions through multiple prescribers or pharmacies. Using spatial autocorrelation and cluster analyses, overdose and PIP hotspots were identified among 538 ZIP codes. RESULTS: More than half of the adult population (n = 3,143,817, ages 18 and older) were prescribed opioids. Nearly all ZIP codes showed increasing rates of overdose over time. Overdose clusters were identified in Worcester, Northampton, Lee/Tyringham, Wareham/Bourne, Lynn, and Revere/Chelsea (Getis-Ord Gi*; p < 0.05). Large PIP clusters for ≥100 MMEs and prescription without pain diagnosis were identified in Western Massachusetts; and smaller clusters for multiple prescribers in Nantucket, Berkshire, and Hampden Counties (p < 0.05). Co-prescriptions and cash payment clusters were localized and nearly identical (p < 0.05). Overlap in PIP and overdose clusters was identified in Cape Cod and Berkshire County. However, we also found contradictory patterns in overdose and PIP hotspots. CONCLUSIONS: Overdose and PIP hotspots were identified, as well as regions where the two overlapped, and where they diverged. Results indicate that PIP clustering alone does not explain overdose clustering patterns. Our findings can inform public health policy decisions at the local level, which include a focus on PIP and misuse of heroin and fentanyl that aim to curb opioid overdoses.

From General to Specific: Can Pseudomonas Primary Metabolism Be Exploited for Narrow-Spectrum Antibiotics?

The spread of antimicrobial resistance is a major threat to human health, and patients requiring prolonged antibiotic exposure are in desperate need of new therapeutic strategies. It has been hypothesized that tailoring our antibiotics to inhibit molecular targets specific to pathogens might stem the spread of resistance. A prime candidate for such a strategy is Pseudomonas aeruginosa, which can be found in the lungs of nearly all adult cystic fibrosis patients and, due to chronic exposure to antibiotics, has a high rate of multidrug-resistant strains. Although much research has been done on P. aeruginosa virulence factors as narrow-spectrum targets, less attention has been paid to primary carbon metabolism being leveraged for pathogen-specific mechanisms. However, early studies show that primary metabolic pathways, although shared amongst all organisms, contain intricacies specific to Pseudomonas species that have potential for antibiotic exploitation. Here we lay out some of this work in the hopes that it inspires researchers to continue developing a knowledge base for future antibiotic discovery to build upon and include a case study of a Pseudomonas primary metabolic pathway that has been targeted by small molecules in a species-specific manner.

An Investigation into Rigidity-Activity Relationships in BisQAC Amphiphilic Antiseptics.

Twenty-one mono- and biscationic quaternary ammonium amphiphiles (monoQACs and bisQACs) were rapidly prepared in order to investigate the effects of rigidity of a diamine core structure on antiseptic activity. As anticipated, the bioactivity against a panel of six bacteria including methicillin-resistant Staphylococcus aureus (MRSA) strains was strong for bisQAC structures, and is clearly correlated with the length of non-polar side chains. Modest advantages were noted for amide-containing side chains, as compared with straight-chained alkyl substituents. Surprisingly, antiseptics with more rigidly disposed side chains, such as those in DABCO-12,12, showed the highest level of antimicrobial activity, with single-digit MIC values or better against the entire bacterial panel, including sub-micromolar activity against an MRSA strain.