Targeting Helicobacter pylori for antibacterial drug discovery with novel therapeutics.

Helicobacter pylori is an important human pathogen with increasing antimicrobial resistance to standard-of-care antibiotics. Treatment generally includes a combination of classical broad-spectrum antibiotics and a proton-pump inhibitor, which often leads to perturbation of the gut microbiome and the potential for the development of antibiotic resistance. In this review, we examine reports, primarily from the past decade, on the discovery of new anti-H.

The Discovery and Development of Thienopyrimidines as Inhibitors of That Act through Inhibition of the Respiratory Complex I.

The successful treatment of infections is becoming increasingly difficult due to the rise of resistance against current broad spectrum triple therapy regimens. In the search for narrow-spectrum agents against , a high-throughput screen identified two structurally related thienopyrimidine compounds that selectively inhibited over commensal members of the gut microbiota. To develop the structure-activity relationship (SAR) of the thienopyrimidines against , this study employed four series of modifications in which systematic substitution to the thienopyrimidine core was explored and ultimately side-chain elements optimized from the two original hits were merged into lead compounds.

Ureadepsipeptides as ClpP Activators.

Acyldepsipeptides are a unique class of antibiotics that act via allosterically dysregulated activation of the bacterial caseinolytic protease (ClpP). The ability of ClpP activators to kill nongrowing bacteria represents a new opportunity to combat deep-seated biofilm infections. However, the acyldepsipeptide scaffold is subject to rapid metabolism.

and Effects of a ClpP-Activating Antibiotic against Vancomycin-Resistant Enterococci.

Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been characterized sufficiently for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance.

In vitro and in vivo activities of HPi1, a selective antimicrobial against Helicobacter pylori.

A high-throughput screen (HTS) was performed to identify molecules specifically active against Helicobacter pylori, the causative agent of peptic ulcer and gastric carcinoma. Currently, treatment of H. pylori infection is suboptimal, with failure rates approaching 25%, despite triple therapy with two broad-spectrum antibiotics and a proton pump inhibitor or quadruple therapy with added bismuth.

Potentiation of azole antifungals by 2-adamantanamine.

Azoles are among the most successful classes of antifungals. They act by inhibiting α-14 lanosterol demethylase in the ergosterol biosynthesis pathway. Oropharyngeal candidiasis (OPC) occurs in about 90% of HIV-infected individuals, and 4 to 5% are refractory to current therapies, including azoles, due to the formation of resistant biofilms produced in the course of OPC.

Novel high-throughput screen against Candida albicans identifies antifungal potentiators and agents effective against biofilms.

Objectives: Microbial adhesion and biofilms have important implications for human health and disease. Candida albicans is an opportunistic pathogen which forms drug-resistant biofilms that contribute to the recalcitrance of disease. We have developed a high-throughput screen for potentiators of clotrimazole, a common therapy for Candida infections, including vaginitis and thrush.

Patients with long-term oral carriage harbor high-persister mutants of Candida albicans.

Fungal biofilms produce a small number of persister cells which can tolerate high concentrations of fungicidal agents. Persisters form upon attachment to a surface, an important step in the pathogenesis of Candida strains. The periodic application of antimicrobial agents may select for strains with increased levels of persister cells.

Candida albicans biofilms produce antifungal-tolerant persister cells.

Fungal pathogens form biofilms that are highly recalcitrant to antimicrobial therapy. The expression of multidrug resistance pumps in young biofilms has been linked to increased resistance to azoles, but this mechanism does not seem to underlie the resistance of mature biofilms that is a model of in vivo infection. The mechanism of drug resistance of mature biofilms remains largely unknown.