Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development.

Conventional antimicrobial discovery relies on targeting essential enzymes in pathogenic organisms, contributing to a paucity of new antibiotics to address resistant strains. Here, by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, to deliver lethal payloads, we expand what can be considered druggable within any pathogen. We synthesized HS-291, an HtpG inhibitor tethered to the photoactive toxin verteporfin.

Inactivation of multidrug-resistant bacteria and bacterial spores and generation of high-potency bacterial vaccines using ultrashort pulsed lasers.

Multidrug-resistant organisms (MDROs) represent a continuing healthcare crisis with no definitive solution to date. An alternative to antibiotics is the development of therapies and vaccines using biocompatible physical methods such as ultrashort pulsed (USP) lasers, which have previously been shown to inactivate pathogens while minimizing collateral damage to human cells, blood proteins, and vaccine antigens. Here we demonstrate that visible USP laser treatment results in bactericidal effect (≥3-log load reduction) against clinically significant MDROs, including methicillin-resistant Staphylococcus aureus and extended spectrum beta-lactamase-producing Escherichia coli.

Structure-guided microbial targeting of antistaphylococcal prodrugs.

Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential.

The active repertoire of Escherichia coli peptidoglycan amidases varies with physiochemical environment.

Nearly all bacteria are encased in peptidoglycan, an extracytoplasmic matrix of polysaccharide strands crosslinked through short peptide stems. In the Gram-negative model organism Escherichia coli, more than 40 synthases and autolysins coordinate the growth and division of the peptidoglycan sacculus in the periplasm. The precise contribution of many of these enzymes to peptidoglycan metabolism remains unclear due to significant apparent redundancy, particularly among the autolysins.

Bacterial Cell Wall Quality Control during Environmental Stress.

Single-celled organisms must adapt their physiology to persist and propagate across a wide range of environmental conditions. The growth and division of bacterial cells depend on continuous synthesis of an essential extracellular barrier: the peptidoglycan cell wall, a polysaccharide matrix that counteracts turgor pressure and confers cell shape. Unlike many other essential processes and structures within the bacterial cell, the peptidoglycan cell wall and its synthesis machinery reside at the cell surface and are thus uniquely vulnerable to the physicochemical environment and exogenous threats.

Peptidoglycan editing provides immunity to during bacterial warfare.

Peptidoglycan (PG) is essential in most bacteria. Thus, it is often targeted by various assaults, including interbacterial attacks via the type VI secretion system (T6SS). Here, we report that the Gram-negative bacterium strain ATCC 17978 produces, secretes, and incorporates the noncanonical d-amino acid d-lysine into its PG during stationary phase.

pH-dependent activation of cytokinesis modulates Escherichia coli cell size.

Cell size is a complex trait, derived from both genetic and environmental factors. Environmental determinants of bacterial cell size identified to date primarily target assembly of cytosolic components of the cell division machinery. Whether certain environmental cues also impact cell size through changes in the assembly or activity of extracytoplasmic division proteins remains an open question.

Plasticity of cell wall metabolism promotes fitness and antibiotic resistance across environmental conditions.

Unlabelled: Although the peptidoglycan cell wall is an essential structural and morphological feature of most bacterial cells, the extracytoplasmic enzymes involved in its synthesis are frequently dispensable under standard culture conditions. By modulating a single growth parameter-extracellular pH-we discovered a subset of these so-called 'redundant' enzymes in are required for maximal fitness across pH environments. Among these pH specialists are the class A penicillin binding proteins PBP1a and PBP1b; defects in these enzymes attenuate growth in alkaline and acidic conditions, respectively.

Evolving to End a Toxic Relationship: ADP Ribosylation in Interbacterial Warfare.

Long before pathogenic interactions with eukaryotic cells evolved, bacteria were competing with one another for limited resources. In this issue, Ting et al. (2018) identify previously unappreciated players in the interbacterial arms race that may be the evolutionary ancestors of eukaryotic cell-targeting ADP-ribosyltransferase toxins.

Temporal and Racial Differences Associated with Atopic Dermatitis and Encoded Virulence Factors.

Atopic dermatitis (AD) is an inflammatory skin condition strongly associated with colonization and infection. strains shift in populations in ~10-year intervals depending on virulence factors. Shifts in virulence factors may in part explain the racial differences observed in the levels of prevalence and severity of AD.

Toxic shock syndrome toxin-1, not α-toxin, mediated Bundaberg fatalities.

The 1928 Bundaberg disaster is one of the greatest vaccine tragedies in history. Of 21 children immunized with a diphtheria toxin-antitoxin preparation contaminated with Staphylococcus aureus, 18 developed life-threatening disease and 12 died within 48  h. Historically, the deaths have been attributed to α-toxin, a secreted cytotoxin produced by most S.

Non-aqueous glycerol monolaurate gel exhibits antibacterial and anti-biofilm activity against Gram-positive and Gram-negative pathogens.

Background: Skin and surgical infections due to Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii are causes of patient morbidity and increased healthcare costs. These organisms grow planktonically and as biofilms, and many strains exhibit antibiotic resistance. This study examines the antibacterial and anti-biofilm activity of glycerol monolaurate (GML), as solubilized in a non-aqueous vehicle (5% GML Gel), as a novel, broadly-active topical antimicrobial.

Menaquinone analogs inhibit growth of bacterial pathogens.

Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four of these organisms to develop novel topical antibacterial agents that interfere with growth and exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, and coenzymes Q1 to Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the growth and to a greater extent exotoxin production of Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, and Streptococcus agalactiae at concentrations of 10 to 200 μg/ml.