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1.
Eur J Med Chem Rep ; 112024 Aug.
Article in English | MEDLINE | ID: mdl-38962287

ABSTRACT

Globally, millions of infections that are resistant to antimicrobial agents are reported annually, leading to more than 700,000 fatalities. Among all, challenges arise particularly from nontuberculosis mycobacterial (NTM) and Gram-negative bacteria, as they exhibit limited treatment options in light of increasing reports of multi-drug resistant strains. Clofazimine (CFZ) is an antimycobacterial medication used to treat leprosy, and it is also known for its side effect of inducing skin pigmentation. The use of CFZ and its analogues against a broad range of Gram-negative bacteria has not been extensively investigated. In this study, we designed, synthesized and studied 11 CFZ analogues and identified examples with comparable or improved in vitro anti-bacterial activity relative to that of CFZ itself. This is the first report demonstrating in vitro activity of CFZ and its analogues against Neisseria species. The results of these studies may facilitate the development of CFZ analogues with limited side effects in humans.

2.
Microbiol Spectr ; 11(6): e0228223, 2023 Dec 12.
Article in English | MEDLINE | ID: mdl-37982630

ABSTRACT

IMPORTANCE: New drugs are needed to combat multidrug-resistant tuberculosis. The electron transport chain (ETC) maintains the electrochemical potential across the cytoplasmic membrane and allows the production of ATP, the energy currency of any living cell. The mycobacterial engine F-ATP synthase catalyzes the formation of ATP and has come into focus as an attractive and rich drug target. Recent deep insights into these mycobacterial F1FO-ATP synthase elements opened the door for a renaissance of structure-based target identification and inhibitor design. In this study, we present the GaMF1.39 antimycobacterial compound, targeting the rotary subunit γ of the biological engine. The compound is bactericidal, inhibits infection ex vivo, and displays enhanced anti-tuberculosis activity in combination with ETC inhibitors, which promises new strategies to shorten tuberculosis chemotherapy.


Subject(s)
Clofazimine , Mycobacterium tuberculosis , Clofazimine/pharmacology , Clofazimine/therapeutic use , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Adenosine Triphosphate
3.
Biometals ; 36(2): 315-320, 2023 04.
Article in English | MEDLINE | ID: mdl-35229216

ABSTRACT

Despite advances in chemotherapeutic interventions for the treatment of malaria, there is a continuing need for the development of new antimalarial agents. Previous studies indicated that co-administration of chloroquine with antioxidants such as the iron chelator deferoxamine (DFO) prevented the development of persistent cognitive damage in surrogate models of cerebral malaria. The work described herein reports the syntheses and antimalarial activities of covalent conjugates of both natural (siderophores) and artificial iron chelators, namely DFO, ferricrocin and ICL-670, with antimalarial 1,2,4-trioxolanes (ozonides). All of the synthesized conjugates had potent antimalarial activities against the in vitro cultures of drug resistant and drug sensitive strains of Plasmodium falciparum. The work described herein provides the basis for future development of covalent combination of iron chelators and antimalarial chemotherapeutic agents for the treatment of cerebral malaria.


Subject(s)
Antimalarials , Malaria, Cerebral , Humans , Antimalarials/pharmacology , Antimalarials/therapeutic use , Siderophores/pharmacology , Malaria, Cerebral/drug therapy , Amides , Esters , Iron Chelating Agents/pharmacology , Iron Chelating Agents/therapeutic use
4.
Bioorg Chem ; 128: 106074, 2022 11.
Article in English | MEDLINE | ID: mdl-35987188

ABSTRACT

The imidazo[1,2-a]pyridine-3-carboxyamides (IAPs) are a unique class of compounds endowed with impressive nanomolar in vitro potency against Mycobacterium tuberculosis (Mtb) as exemplified by clinical candidate Telacebec (Q203). These compounds target mycobacterial respiration through inhibition of the QcrB subunit of cytochrome bc1:aa3 super complex resulting in bacteriostatic efficacy in vivo. Our labs have had a long-standing interest in the design and development of IAPs. However, some of these compounds suffer from short in vivo half-lives, requiring multiple daily dosing or the addition of a cytochrome P450 inhibitor for murine efficacy evaluations. Deuteration has been shown to decrease metabolism as the C-D bond is stronger than the CH bond. Herein we describe our efforts on design and synthesis of potent deuterated IAPs and the effect that deuteration has upon metabolism through microsomal stability studies.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Antitubercular Agents/chemistry , Humans , Mice , Pyridines/metabolism , Pyridines/pharmacology , Tuberculosis/microbiology
5.
Clin Nutr ESPEN ; 48: 227-233, 2022 04.
Article in English | MEDLINE | ID: mdl-35331496

ABSTRACT

BACKGROUND AND AIMS: Metabolic Bone Disease of Infancy is a multifactorial disorder of bone fragility in infants who typically present under 6 months of age with multiple unexplained fractures. Major risk factors for this disorder relate to the fetal time period and include decreased provision of the essential nutrients for bone formation during pregnancy (calcium, phosphate, vitamin D, and protein), prematurity, and decreased fetal bone loading. METHODS: This study presents 5 infants with multiple unexplained fractures born to women who had prior bariatric surgery in which child abuse was alleged, and the alleged perpetrator denied wrong doing. RESULTS: The radiographic findings showed poor bone mineralization and were consistent with Metabolic Bone Disease of Infancy. CONCLUSIONS: Using the Utah Paradigm to understand risk factors for MBDI, the authors believe the nutritional deficiencies that accompany bariatric surgery likely contribute to the bone fragility in these 5 infants. Other risk factors for MBDI were appreciated in 4 of the 5 cases. 1,25 dihydroxyvitamin D was elevated or high-normal suggesting calcium deficiency in 2 cases. We believe infants born to mothers who have had prior bariatric surgery are at increased risk for bone fragility and MBDI during the first 6 months of life.


Subject(s)
Bariatric Surgery , Bone Diseases, Metabolic , Child Abuse , Bariatric Surgery/adverse effects , Bone Diseases, Metabolic/diagnostic imaging , Bone Diseases, Metabolic/etiology , Bone and Bones/diagnostic imaging , Child , Female , Humans , Infant , Mothers , Pregnancy
6.
ACS Infect Dis ; 7(11): 2979-2986, 2021 11 12.
Article in English | MEDLINE | ID: mdl-34668698

ABSTRACT

Monocyclic ß-lactams with antibiotic activity were first synthesized more than 40 years ago. Extensive early structure-activity relationship (SAR) studies, especially in the 1980s, emphasized the need for heteroatom activation of monocyclic ß-lactams and led to studies of oxamazins, monobactams, monosulfactams, and monocarbams with various side chains and peripheral substitution that revealed potent activity against select strains of Gram-negative bacteria. Aztreonam, still the only clinically used monobactam, has notable activity against many Gram-negative bacteria but limited activity against some of the most problematic multidrug resistant (MDR) strains of Pseudomonas aeruginosa and Acinetobacter baumannii. Herein, we report that extension of the side chain of aztreonam is tolerated and especially that coupling of the side chain free acid with a bis-catechol siderophore mimetic significantly improves activity against the MDR strains of Gram-negative bacteria that are of most significant concern.


Subject(s)
Aztreonam , Monobactams , Anti-Bacterial Agents/pharmacology , Aztreonam/pharmacology , Gram-Negative Bacteria , Microbial Sensitivity Tests , Monobactams/pharmacology , Siderophores
7.
RSC Med Chem ; 12(1): 62-72, 2021 Jan 01.
Article in English | MEDLINE | ID: mdl-34046598

ABSTRACT

The formation efficiency of hydride-induced Meisenheimer complexes of nitroaromatic compounds is consistent with their anti-TB activities exemplied by MDL860 and benzothiazol N-oxide (BTO) analogs. Herein we report that nitro cyano phenoxybenzenes (MDL860 and analogs) reacted slowly and incompletely which reflected their moderate anti-TB activity, in contrast to the instantaneous reaction of BTO derivatives to quantitatively generate Meisenheimer complexes which corresponded to their enhanced anti-TB activity. These results were corroborated by mycobacterial and radiolabelling studies that confirmed inhibition of the DprE1 enzyme by BTO derivatives but not MDL860 analogs.

8.
RSC Med Chem ; 12(1): 73-77, 2021 Jan 01.
Article in English | MEDLINE | ID: mdl-34046599

ABSTRACT

Cytochrome bd oxidase (Cyt-bd) is an attractive drug target in Mycobacterium tuberculosis, especially in the context of developing a drug combination targeting energy metabolism. However, currently few synthetically assessable scaffolds target Cyt-bd. Herein, we report that thieno[3,2-d]pyrimidin-4-amines inhibit Cyt-bd, and report an initial structure-activity-relationship (SAR) of 13 compounds in three mycobacterial strains: Mycobacterium bovis BCG, Mycobacterium tuberculosis H37Rv and Mycobacterium tuberculosis clinical isolate N0145 in an established ATP depletion assay with or without the cytochrome bcc : aa 3 (QcrB) inhibitor Q203. All compounds displayed activity against M. bovis BCG and the M. tuberculosis clinical isolate strain N0145 with ATP IC50 values from 6 to 54 µM in the presence of Q203 only, as expected from a Cyt-bd inhibitor. All derivatives were much less potent against M. tuberculosis H37Rv compared to N0145 (IC50's from 24 to >100 µM and 9-52 µM, respectively), an observation that may be attributed to the higher expression of the Cyt-bd-encoding genes in the laboratory-adapted M. tuberculosis H37Rv strain. N-(4-(tert-butyl)phenethyl)thieno[3,2-d]pyrimidin-4-amine (19) was the most active compound with ATP IC50 values from 6 to 18 µM against all strains in the presence of Q203, making it a good chemical probe for interrogation the function of the mycobacterial Cyt-bd under various physiological conditions.

10.
Acc Chem Res ; 54(7): 1646-1661, 2021 04 06.
Article in English | MEDLINE | ID: mdl-33684288

ABSTRACT

This Account describes fundamental chemistry that promoted the discovery of new antibiotics. Specifically, the NH acidity of simple hydroxamic acid derivatives facilitated the syntheses of novel ß-lactams (oxamazins and monobactams), siderophore mimics that limit bacterial iron uptake and bacterially targeted sideromycins (siderophore-antibiotic conjugates). The development of resistance to our current limited set of antibiotic scaffolds has created a dire medical situation. As recently stated, "if you weren't taking antibiotic resistance seriously before, now would be a good time to start." A project commissioned by the British government (https://amr-review.org/) has released estimates of the near-future global toll of antibiotic resistance that are jaw-dropping in their seriousness and scale: 10 million deaths per year and at least $100 trillion in sacrificed gross national product. The 2020 COVID pandemic confirmed that infectious disease problems are no longer localized but worldwide. Many classical antibiotics, especially ß-lactams, previously provided economical cures, but the evolution of antibiotic destructive enzymes (i.e., ß-lactamases), efflux pumps, and bacterial cell wall permeability barriers has made many types of bacteria, especially Gram-negative strains, resistant. Still, and in contrast to other therapies, the public expectation is that any new antibiotic must be inexpensive. This creates market limitations that have caused most major pharmaceutical companies to abandon antibiotic research. Much needs to be done to address this significant problem.The critical need for bacteria to sequester essential iron provides an Achilles' heel for new antibiotic development. Although ferric iron is extremely insoluble, bacteria need micromolar intracellular concentrations for growth and virulence. To this end, they biosynthesize siderophores (Gr. iron bearer) and excrete them into their environment, where they bind iron with high affinity. The iron complexes are recognized by specific outer-membrane transporters, and once actively internalized, the iron is released for essential processes. To conserve biosynthetic energy, some bacteria recognize and utilize siderophores made by competing strains. As a counter-revolution in the never-ending fight for survival, bacteria have also evolved sideromycins, which are siderophores conjugated to warheads that are lethal to rogue bacteria. While none are now used therapeutically, natural sideromycins called albomycins have been used clinically, and others have been shown to be well tolerated and active in animal infection models. Herein we describe practical methods to synthesize new antibiotics and artificial sideromycins with the generalized structure shown above (siderophore-linker drug). Utilizing the molecular-recognition-based siderophore/sideromycin bacterial assimilation processes, it is possible to design both broad spectrum and exquisitely narrow spectrum (targeted) sideromycins and even repurpose older or more classical antibiotics. Relevant microbiological assays, in vivo animal infection studies, and the recent FDA approval of cefiderocol demonstrate their effectiveness.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Drug Design , Ferrous Compounds/pharmacology , Iron Compounds/pharmacology , Peptides/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Ferrous Compounds/chemical synthesis , Ferrous Compounds/chemistry , Humans , Iron Compounds/chemical synthesis , Iron Compounds/chemistry , Microbial Sensitivity Tests , Molecular Structure , Peptides/chemical synthesis , Peptides/chemistry
11.
Appl Sci (Basel) ; 11(19)2021 Oct.
Article in English | MEDLINE | ID: mdl-36698770

ABSTRACT

The development of cytochrome bd oxidase (cyt-bd) inhibitors are needed for comprehensive termination of energy production in Mycobacterium tuberculosis (Mtb) to treat tuberculosis infections. Herein, we report on the structure-activity-relationships (SAR) of 22 new N-phenethyl-quinazolin-4-yl-amines that target cyt-bd. Our focused set of compounds was synthesized and screened against three mycobacterial strains: Mycobacterium bovis BCG, Mycobacterium tuberculosis H37Rv and the clinical isolate Mycobacterium tuberculosis N0145 with and without the cytochrome bcc:aa 3 inhibitor Q203 in an ATP depletion assay. Two compounds, 12a and 19a, were more active against all three strains than the naturally derived cyt-bd inhibitor aurachin D.

12.
EMBO Mol Med ; 13(1): e13207, 2021 01 11.
Article in English | MEDLINE | ID: mdl-33283973

ABSTRACT

The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F1 F0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from Q203-induced death, highlighting the attractiveness of the bd-type terminal oxidase for drug development. Here, we employed a facile whole-cell screen approach to identify the cytochrome bd inhibitor ND-011992. Although ND-011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic-tolerant, non-replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Anti-Bacterial Agents , Antitubercular Agents/pharmacology , Electron Transport Complex IV/metabolism , Mice , Oxidoreductases , Tuberculosis/drug therapy
13.
Pathogens ; 9(10)2020 Sep 30.
Article in English | MEDLINE | ID: mdl-33007866

ABSTRACT

Siderophores produced in soil by plant growth-promoting rhizobacteria (PGPRs) play several roles, including nutrient mobilizers and can be useful as plants defense elicitors. We investigated the role of a synthetic mixed ligand bis-catechol-mono-hydroxamate siderophore (SID) that mimics the chemical structure of a natural siderophore, fimsbactin, produced by Acinetobacter spp. in the resistance against the phytopathogen Pseudomonas syringaepv tomato DC3000 (Pst DC3000), in Arabidopsis thaliana. We first tested the antibacterial activity of SID against Pst DC3000 in vitro. After confirming that SID had antibacterial activity against Pst DC3000, we tested whether the observed in vitro activity could translate into resistance of Arabidopsis to Pst DC3000, using bacterial loads as endpoints in a plant infection model. Furthermore, using quantitative polymerase chain reaction, we explored the molecular actors involved in the resistance of Arabidopsis induced by SID. Finally, to assure that SID would not interfere with PGPRs, we tested in vitro the influence of SID on the growth of a reference PGPR, Bacillus subtilis. We report here that SID is an antibacterial agent as well as an inducer of systemic priming of resistance in A. thaliana against Pst DC3000, and that SID can, at the same time, promote growth of a PGPR.

14.
Acta Crystallogr C Struct Chem ; 76(Pt 9): 907-913, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32887862

ABSTRACT

1,3-Benzothiazin-4-ones (BTZs) are a promising new class of drugs with activity against Mycobacterium tuberculosis, which have already reached clinical trials. A product obtained in low yield upon treatment of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzothiazin-4-one with 3-chloroperbenzoic acid, in analogy to a literature report describing the formation of sulfoxide and sulfone derived from BTZ043 [Tiwari et al. (2015). ACS Med. Chem. Lett. 6, 128-133], is a ring-contracted benzisothiazolinone (BIT) 1-oxide, namely, 7-nitro-2-(piperidine-1-carbonyl)-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one 1-oxide, C14H12F3N3O5S, as revealed by X-ray crystallography. Single-crystal X-ray analysis of the oxidation product originally assigned as BTZ043 sulfone provides clear evidence that the structure of the purported BTZ043 sulfone is likewise the corresponding BIT 1-oxide, namely, 2-[(S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carbonyl]-7-nitro-5-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one 1-oxide, C17H16F3N3O7S. A possible mechanism for the ring contraction affording the BIT 1-oxides instead of the anticipated constitutionally isomeric BTZ sulfones and antimycobacterial activities thereof are discussed.

16.
PLoS One ; 15(1): e0227224, 2020.
Article in English | MEDLINE | ID: mdl-31905374

ABSTRACT

The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.5 µM and mono-drug resistant potency ranging from 0.0017 to 7 µM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng·hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.


Subject(s)
Antitubercular Agents/therapeutic use , Imidazoles/therapeutic use , Mycobacterium tuberculosis/drug effects , Thiazoles/therapeutic use , Tuberculosis/drug therapy , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Caco-2 Cells , Chlorocebus aethiops , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme Inhibitors/therapeutic use , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Microbial Sensitivity Tests , Mycobacterium tuberculosis/growth & development , RAW 264.7 Cells , Thiazoles/chemistry , Thiazoles/pharmacology , Vero Cells
17.
J Antibiot (Tokyo) ; 73(3): 152-157, 2020 03.
Article in English | MEDLINE | ID: mdl-31836835

ABSTRACT

Antibiotics that are normally used to treat infections caused by Gram-positive bacteria might be made effective against Gram-negative bacterial infections, if they can circumvent permeability barriers and antibiotic deactivation processes associated with Gram-negative bacteria. Herein we report syntheses of bis-catechol-teicoplanin and mixed ligand catechol-hydroxamate-teicoplanin conjugates. Antibacterial activity assays revealed that conjugation of teicoplanin, which is only known to be active against Gram-positive bacteria, to the siderophore mimics induced potent activity against multidrug resistant strains of select Gram-negative bacteria (Acinetobacter baumannii) while retaining moderate activity against Gram-positive bacteria (Staphylococcus aureus).


Subject(s)
Acinetobacter baumannii/drug effects , Anti-Bacterial Agents/pharmacology , Catechols/chemistry , Drug Resistance, Multiple, Bacterial , Teicoplanin/analogs & derivatives , Teicoplanin/pharmacology , Anti-Bacterial Agents/chemistry , Drug Repositioning , Ligands , Microbial Sensitivity Tests , Molecular Structure , Teicoplanin/chemistry
18.
Mol Carcinog ; 59(2): 193-201, 2020 02.
Article in English | MEDLINE | ID: mdl-31782573

ABSTRACT

Gartanin, a 4-prenylated xanthone, has been identified from the purple mangosteen fruit as a potent growth inhibitor of various cancer cell lines, including prostate cancer. However, much of Gartanin's anticancer mechanism remains unknown. We have discovered that Gartanin docked onto the regulatory subunit of the precursor cell-expressed developmentally downregulated 8 (NEDD8)-activating enzyme (NAE) complex and next to the NEDD8 binding complex, which leads to inhibit NEDD8 conjugations to both Cullin1 and Ubc12 in prostate cancer cell lines and Ubc12 NEDDylation in an in vitro assay. The S phase kinase-associated protein (Skp2) and F-box and WD-repeat domain-containing 2 (FBXW2), the NEDD8 family members of E3 ubiqutin ligases, were also downregulated and upregulated by Gartainin, respectively. Knock-down of NEDD8 expression by short harpin (Sh) RNAs blocked or attenuated these effects of Gartainin. Finally, Gartanin demonstrated its ability to inhibit growth of prostate cancer lines via autophagy initiation. Our data support that Gartanin is a naturally occurring NEDDylation inhibitor and deserves further investigation for prostate cancer prevention and treatment.


Subject(s)
Autophagy/drug effects , F-Box Proteins/metabolism , NEDD8 Protein/antagonists & inhibitors , Prostatic Neoplasms/metabolism , S-Phase Kinase-Associated Proteins/metabolism , Xanthones/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , F-Box Proteins/genetics , Humans , Male , NEDD8 Protein/metabolism , PC-3 Cells , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , RNA Interference
19.
Anal Methods ; 11(3): 296-302, 2019 Jan 21.
Article in English | MEDLINE | ID: mdl-31666814

ABSTRACT

A siderophore-based active bacterial pull-down strategy was integrated in a localized surface plasmon resonance (LSPR) sensing platform and subsequently tested by detecting whole-cell Acinetobacter baumannii. The LSPR-based whole-cell sensing approach was previously demonstrated with aptamer-based molecular recognition motifs, and here it is extended to the powerful siderophore system, which exploits the natural bacterial need to sequester Fe(III). Specifically, a biscatecholate-monohydroxamate mixed ligand siderophore linked to a biotin via three polyethylene glycol repeating units was synthesized and immobilized on Au trigonal nanoprisms of an LSPR sensor. The resulting surface-confined biotinylated siderophore subsequently chelated Fe(III), forming a siderophore-Fe(III) complex which was shown to be competent to recognize A. baumannii. Target bacteria were captured and then detected by measuring wavelength shifts in the LSPR extinction spectrum. This siderophore pull-down LSPR biosensor approach is rapid (≤3 h detection) and sensitive - with a limit of detection (LOD) of 80 bacterial cells and a linear wavelength shift over the range 4 × 102 to 4 × 106 cfu mL-1. As intended by design, the siderophore-based biosensor was selective for A. baumannii over Pseudomonas aeruginosa, Escherichia coli, and Bacillus cereus, and was stable in ambient conditions for up to 2 weeks.

20.
ACS Med Chem Lett ; 10(10): 1462-1466, 2019 Oct 10.
Article in English | MEDLINE | ID: mdl-31620234

ABSTRACT

Substituted nitrobenzothiazinones (BTZs) are potent antituberculosis prodrugs that are reductively activated to produce nitroso moieties that form covalent adducts with a cysteine residue of decaprenylphosphoryl-ß-d-ribose-2'-oxidase (DprE1) of Mycobacterium tuberculosis (Mtb). The resulting cell wall synthesis inhibition is lethal to Mtb, leading to consideration of development of BTZs for clinical use. The hydride-induced reduction of the nitroaromatic proceeds by reversible formation of the corresponding Meisenheimer complex. Herein we demonstrate that chemical reduction of BTZ043 with NaBD4 followed by reoxidation incorporates deuterium into the core nitro aromatic warhead. Subsequent reduction of the deuterated species is not affected, but, as expected, reoxidation is slowed by the deuterium isotope effect, thus prolonging the lifetime of the active nitroso oxidation state.

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