Synthesis and Structure-Activity Studies of β-Barrel Assembly Machine Complex Inhibitor MRL-494.

In the hunt for new antibiotics with activity against Gram-negative pathogens, the outer membrane β-barrel assembly machine (BAM) complex has become an increasingly interesting target. The recently reported BAM complex inhibitor, MRL-494, was discovered via a screening campaign for molecules that target the outer membrane. Notably, MRL-494 was reported to be an unintended byproduct generated during the synthesis of an unrelated compound, and as such no synthesis of the compound was disclosed.

Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex.

The use of antibiotics is threatened by the emergence and spread of multidrug-resistant strains of bacteria. Thus, there is a need to develop antibiotics that address new targets. In this respect, the bacterial divisome, a multi-protein complex central to cell division, represents a potentially attractive target.

Overexpression of the Bam Complex Improves the Production of MOMP in the Outer Membrane.

A licensed vaccine is not yet available. Recombinant major outer membrane protein (-MOMP), the most abundant constituent of the chlamydial outer membrane complex, is considered the most attractive candidate for subunit-based vaccine formulations. Unfortunately, -MOMP is difficult to express in its native structure in the outer membrane (OM).

Eeyarestatin 24 impairs SecYEG-dependent protein trafficking and inhibits growth of clinically relevant pathogens.

Eeyarestatin 1 (ES1) is an inhibitor of endoplasmic reticulum (ER) associated protein degradation, Sec61-dependent Ca homeostasis and protein translocation into the ER. Recently, evidence was presented showing that a smaller analog of ES1, ES24, targets the Sec61-translocon, and captures it in an open conformation that is translocation-incompetent. We now show that ES24 impairs protein secretion and membrane protein insertion in Escherichia coli via the homologous SecYEG-translocon.

Distinct Requirements for Tail-Anchored Membrane Protein Biogenesis in Escherichia coli.

Tail-anchored membrane proteins (TAMPs) are a distinct subset of inner membrane proteins (IMPs) characterized by a single C-terminal transmembrane domain (TMD) that is responsible for both targeting and anchoring. Little is known about the routing of TAMPs in bacteria. Here, we have investigated the role of TMD hydrophobicity in tail-anchor function in and its influence on the choice of targeting/insertion pathway.