Discovery and Derivatization of Tridecaptin Antibiotics with Altered Host Specificity and Enhanced Bioactivity.

The prevalence of multidrug-resistant (MDR) pathogens combined with a decline in antibiotic discovery presents a major challenge for health care. To refill the discovery pipeline, we need to find new ways to uncover new chemical entities. Here, we report the global genome mining-guided discovery of new lipopeptide antibiotics tridecaptin A and tridecaptin D, which exhibit unusual bioactivities within their class.

OmpR facilitates lung infection through transcriptional regulation of key virulence factors.

Bacteria use two-component regulatory systems (TCSs) to adapt to changes in their environment by changing their gene expression. In this study, we show that the EnvZ/OmpR TCS of the clinically relevant opportunistic pathogen plays an important role in successfully establishing lung infection and virulence. In addition, we elucidate the OmpR regulon within the host.

Total Synthesis and Structure Assignment of the Relacidine Lipopeptide Antibiotics and Preparation of Analogues with Enhanced Stability.

The unabated rise of antibiotic resistance has raised the specter of a post-antibiotic era and underscored the importance of developing new classes of antibiotics. The relacidines are a recently discovered group of nonribosomal lipopeptide antibiotics that show promising activity against Gram-negative pathogens and share structural similarities with brevicidine and laterocidine. While the first reports of the relacidines indicated that they possess a C-terminal five-amino acid macrolactone, an N-terminal lipid tail, and an overall positive charge, no stereochemical configuration was assigned, thereby precluding a full structure determination.

Targeting virulence regulation to disarm pathogenesis.

The development of anti-virulence drug therapy against infections would provide an alternative to traditional antibacterial therapy that are increasingly failing. Here, we demonstrate that the OmpR transcriptional regulator plays a pivotal role in the pathogenesis of diverse clinical strains in multiple murine and invertebrate infection models. We identified OmpR-regulated genes using RNA sequencing and further validated two genes whose expression can be used as robust biomarker to quantify OmpR inhibition in .

Design and synthesis of water-soluble prodrugs of rifabutin for intraveneous administration.

Acinetobacter baumannii is a gram-negative bacterium causing severe hospital-acquired infections such as bloodstream infections or pneumonia. Moreover, multidrug resistant A. baumannii becomes prevalent in many hospitals.

The Role of OmpR in Bile Tolerance and Pathogenesis of Adherent-Invasive .

Gut microbiota dysbiosis toward adherent-invasive (AIEC) plays an important role in Crohn's disease (CD). The OmpR transcriptional regulator is required for the AIEC LF82 prototype strain to adhere and invade intestinal epithelial cells. In this study, we explored the role of OmpR in AIEC pathogenesis using a panel of eight strains isolated from CD patients and identified as AIEC.

Rifabutin for infusion (BV100) for the treatment of severe carbapenem-resistant Acinetobacter baumannii infections.

Rifamycin antibiotics were discovered during the 1950s, and their main representative, rifampicin, remains a cornerstone treatment for TB. The clinical use of rifamycin is restricted to mycobacteria and Gram-positive infections because of its poor ability to penetrate the Gram-negative outer membrane. Rifabutin, a rifamycin antibiotic approved for the prevention of Mycobacterium avium complex disease, makes an exception to this rule by hijacking the iron uptake system of Acinetobacter baumannii, resulting in potent activity against this important Gram-negative pathogen.

In vitro activity of rifabutin against 293 contemporary carbapenem-resistant Acinetobacter baumannii clinical isolates and characterization of rifabutin mode of action and resistance mechanisms.

Background: Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled by rifabutin cellular uptake through the siderophore receptor FhuE.

Objectives: To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates.

Dissecting Colistin Resistance Mechanisms in Extensively Drug-Resistant Acinetobacter baumannii Clinical Isolates.

Nosocomial infections with are a global problem in intensive care units with high mortality rates. Increasing resistance to first- and second-line antibiotics has forced the use of colistin as last-resort treatment, and increasing development of colistin resistance in has been reported. We evaluated the transcriptional regulator PmrA as potential drug target to restore colistin efficacy in Deletion of restored colistin susceptibility in 10 of the 12 extensively drug-resistant clinical isolates studied, indicating the importance of PmrA in the drug resistance phenotype.

Quantitative contribution of efflux to multi-drug resistance of clinical Escherichia coli and Pseudomonas aeruginosa strains.

Background: Efflux pumps mediate antimicrobial resistance in several WHO critical priority bacterial pathogens. However, most available data come from laboratory strains. The quantitative relevance of efflux in more relevant clinical isolates remains largely unknown.

Alternative Evolutionary Paths to Bacterial Antibiotic Resistance Cause Distinct Collateral Effects.

When bacteria evolve resistance against a particular antibiotic, they may simultaneously gain increased sensitivity against a second one. Such collateral sensitivity may be exploited to develop novel, sustainable antibiotic treatment strategies aimed at containing the current, dramatic spread of drug resistance. To date, the presence and molecular basis of collateral sensitivity has only been studied in few bacterial species and is unknown for opportunistic human pathogens such as Pseudomonas aeruginosa.

Reversion of antibiotic resistance in by spiroisoxazoline SMARt-420.

Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation.

A Novel Genome-Editing Platform for Drug-Resistant Acinetobacter baumannii Reveals an AdeR-Unrelated Tigecycline Resistance Mechanism.

Infections with the Gram-negative coccobacillus Acinetobacter baumannii are a major threat in hospital settings. The progressing emergence of multidrug-resistant clinical strains significantly reduces the treatment options for clinicians to fight A. baumannii infections.

Engineering of a Synthetic Metabolic Pathway for the Assimilation of (d)-Xylose into Value-Added Chemicals.

A synthetic pathway for (d)-xylose assimilation was stoichiometrically evaluated and implemented in Escherichia coli strains. The pathway proceeds via isomerization of (d)-xylose to (d)-xylulose, phosphorylation of (d)-xylulose to obtain (d)-xylulose-1-phosphate (X1P), and aldolytic cleavage of the latter to yield glycolaldehyde and DHAP. Stoichiometric analyses showed that this pathway provides access to ethylene glycol with a theoretical molar yield of 1.