Mycobacterium tuberculosis must sense and adapt to host environmental cues to establish and maintain an infection. The two-component regulatory system PhoPR plays a central role in sensing and responding to acidic pH within the macrophage and is required for M. tuberculosis intracellular replication and growth in vivo . Therefore, the isolation of compounds that inhibit PhoPR-dependent adaptation may identify new antivirulence therapies to treat tuberculosis. Here, we report that the carbonic anhydrase inhibitor ethoxzolamide inhibits the PhoPR regulon and reduces pathogen virulence. We show that treatment of M. tuberculosis with ethoxzolamide recapitulates phoPR mutant phenotypes, including downregulation of the core PhoPR regulon, altered accumulation of virulence-associated lipids, and inhibition of Esx-1 protein secretion. Quantitative single-cell imaging of a PhoPR-dependent fluorescent reporter strain demonstrates that ethoxzolamide inhibits PhoPR-regulated genes in infected macrophages and mouse lungs. Moreover, ethoxzolamide reduces M. tuberculosis growth in both macrophages and infected mice. Ethoxzolamide inhibits M. tuberculosis carbonic anhydrase activity, supporting a previously unrecognized link between carbonic anhydrase activity and PhoPR signaling. We propose that ethoxzolamide may be pursued as a new class of antivirulence therapy that functions by modulating expression of the PhoPR regulon and Esx-1-dependent virulence.

Staphylococcus pseudintermedius is a commensal bacterium and a major opportunistic pathogen of dogs. The emergence of methicillin-resistant S. pseudintermedius (MRSP) is also becoming a serious concern. We carried out a population genomics study of 130 clinical S. pseudintermedius isolates from dogs and cats in the New England region of the United States. Results revealed the co-circulation of phylogenetically diverse lineages that have access to a large pool of accessory genes. Many MRSP and multidrug-resistant clones have emerged through multiple independent, horizontal acquisition of resistance determinants and frequent genetic exchange that disseminate DNA to the broader population. When compared to a Texas population, we found evidence of clonal expansion of MRSP lineages that have disseminated over large distances. These findings provide unprecedented insight into the diversification of a common cutaneous colonizer of man’s oldest companion animal and the widespread circulation of multiple high-risk resistant clones.

Key Points: Distinct sphingolipid metabolism of AML with MDS-related changes defines unique sensitivity to nanoliposomal C6-ceramide. Vinblastine alters sphingolipid metabolism to enhance the sensitivity of AML to nanoliposomal C6-ceramide.

Escherichia coli biotype O104:H4 recently caused the deadliest E. coli outbreak ever reported. Based on prior results, it was hypothesized that compounds inhibiting biofilm formation by O104:H4 would reduce its pathogenesis. The nonionic surfactants polysorbate 80 (PS80) and polysorbate 20 (PS20) were found to reduce biofilms by ≥ 90% at submicromolar concentrations and elicited nearly complete dispersal of preformed biofilms. PS80 did not significantly impact in vivo colonization in a mouse infection model; however, mice treated with PS80 exhibited almost no intestinal inflammation or tissue damage while untreated mice exhibited robust pathology. As PS20 and PS80 are classified as ‘Generally Recognized as Safe’ (GRAS) compounds by the Food and Drug Administration (FDA), these compounds have clinical potential to treat future O104:H4 outbreaks.

Eleven adult African pygmy hedgehogs (Atelerix albiventris) were added to a group of 35 animals, and within 10 d, respiratory distress affected 8 of 35 resident animals in the group, but none of the introduced animals. Three animals died following onset of clinical signs. Tissues from one animal were collected and submitted for histopathology, which revealed acute necrotizing bronchopneumonia and tracheitis with intraepithelial intranuclear inclusion bodies. Electron microscopy identified 75–90 nm diameter encapsulated icosahedral virions. Degenerate nested PCR analysis identified adenovirus within the affected lung tissue. Deep sequencing showed 100% homology to skunk adenovirus 1 (SkAdV-1). Adenoviruses are usually species-adapted and -specific, but our case supports the single previous report of non-skunk infection with SkAdV-1, indicating that this virus can infect other species, and further shows that it can cause fatal disease.