Cryptogenic Liver Abscess Caused by a K1 Serotype Klebsiella pneumoniae Isolate.

Hypervirulent Klebsiella pneumoniae (hvKp) is a common cause of pyogenic liver abscesses in Asia but is quite uncommon in North America. Among the cases described in North America, only occasional reports have described molecular strain typing to confirm the K1 strain as the causative agent. We report a 56-year-old Hispanic female with no previous intra-abdominal pathology and no recent travel, who presented with subacute abdominal pain and developed bacteremia and monomicrobial pyogenic liver abscess due to a community-acquired K1 serotype K. pneumoniae isolate. In this case, the infection was recognized early, so the patient was successfully treated with percutaneous drainage and prolonged antibiotic therapy. Hvkp can cause severe invasive disease with high morbidity and mortality, and the recent emergence of multidrug resistance in these strains poses a serious threat to public health. In addition, the isolation of a K1 K. pneumoniae strain from a cryptogenic liver abscess in a Hispanic patient with no epidemiologic risk factors raises concern for a wider spread of the hypervirulent strain beyond Asian populations. Therefore, a high index of suspicion for hvKp infection in the Hispanic population can be crucial as the hypervirulent strain is likely to cause severe metastatic infection with significant morbidity and mortality.

The small molecule nitazoxanide selectively disrupts BAM-mediated folding of the outer membrane usher protein.

Bacterial pathogens assemble adhesive surface structures termed pili or fimbriae to initiate and sustain infection of host tissues. Uropathogenic Escherichia coli, the primary causative agent of urinary tract infections, expresses type 1 and P pili required for colonization of the bladder and kidney, respectively. These pili are assembled by the conserved chaperone-usher (CU) pathway, in which a periplasmic chaperone works together with an outer membrane (OM) usher protein to build and secrete the pilus fiber. Previously, we found that the small molecule and antiparasitic drug nitazoxanide (NTZ) inhibits CU pathway-mediated pilus biogenesis in E. coli by specifically interfering with proper maturation of the usher protein in the OM. The usher is folded and inserted into the OM by the ß-barrel assembly machine (BAM) complex, which in E. coli comprises five proteins, BamA-E. Here, we show that sensitivity of the usher to NTZ is modulated by BAM expression levels and requires the BamB and BamE lipoproteins. Furthermore, a genetic screen for NTZ-resistant bacterial mutants isolated a mutation in the essential BamD lipoprotein. These findings suggest that NTZ selectively interferes with an usher-specific arm of the BAM complex, revealing new details of the usher folding pathway and BAM complex function. Evaluation of a set of NTZ derivatives identified compounds with increased potency and disclosed that NTZ's nitrothiazole ring is critical for usher inhibition. In summary, our findings indicate highly specific effects of NTZ on the usher folding pathway and have uncovered NTZ analogs that specifically decrease usher levels in the OM.

Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili.

The chaperone-usher (CU) pathway is a conserved secretion system dedicated to the assembly of a superfamily of virulence-associated surface structures by a wide range of Gram-negative bacteria. Pilus biogenesis by the CU pathway requires two specialized assembly components: a dedicated periplasmic chaperone and an integral outer membrane assembly and secretion platform termed the usher. The CU pathway assembles a variety of surface fibers, ranging from thin, flexible filaments to rigid, rod-like organelles. Pili typically act as adhesins and function as virulence factors that mediate contact with host cells and colonization of host tissues. Pilus-mediated adhesion is critical for early stages of infection, allowing bacteria to establish a foothold within the host. Pili are also involved in modulation of host cell signaling pathways, bacterial invasion into host cells, and biofilm formation. Pili are critical for initiating and sustaining infection and thus represent attractive targets for the development of antivirulence therapeutics. Such therapeutics offer a promising alternative to broad-spectrum antibiotics and provide a means to combat antibiotic resistance and treat infection while preserving the beneficial microbiota. A number of strategies have been taken to develop antipilus therapeutics, including vaccines against pilus proteins, competitive inhibitors of pilus-mediated adhesion, and small molecules that disrupt pilus biogenesis. Here we provide an overview of the function and assembly of CU pili and describe current efforts aimed at interfering with these critical virulence structures.