Fitness barriers to spread of colistin resistance overcome by first establishing niche in patients with enhanced colistin exposure

AbstractThere is an urgent need to improve our understanding of how new antibiotic resistant organisms emerge and spread. A high-priority resistance threat is the ST258 lineage of carbapenem-resistant Klebsiella pneumoniae. Here, we studied resistance to the last-line drug colistin among ST258 by tracking its evolution across 21 U.S. hospitals over the course of a year. Phylogenetic analysis supported a significant fitness cost being associated with resistance, as resistance emergence was common but resistance variants were rarely transmitted. Furthermore, several resistance variants that were transmitted had acquired secondary variants that reverted the strain to susceptible. The exceptions to the general pattern of instability associated with resistance were two large clusters of resistant strains in one sublineage (clade IIB) present across Southern California hospitals. Quantification of transmission fitness in the healthcare environment indicated that, while resistant isolates from other clades were less fit than their susceptible counterparts, clade IIB resistant isolates were more fit, despite having similar resistance variants. Additional analyses supported the increased fitness of colistin-resistant clade IIB isolates being driven by a lineage-defining variant that increased clade IIB’s association with patient subpopulations with enhanced colistin exposure. These results show that a favorable genetic background and sustained selective pressure led to the emergence and spread of a colistin-resistant ST258 sublineage across a regional healthcare network. These findings highlight the utility of integrating pathogen genomic and corresponding clinical data from regional healthcare networks to detect emerging antibiotic resistance threats and understand the clinical practices and patient populations that drive their spread.Significance StatementSelective pressure in hospitals leads to frequent antibiotic resistance evolution. However, emergent resistance alleles are often not transmitted to other individuals because of fitness costs associated with resistance. Due to the difficulty of studying pathogen fitness in humans, our understanding of how resistant organisms circumvent these costs is limited. We integrate genomic and clinical data to understand the evolutionary trajectories leading to transmissible resistance for the last-line antibiotic colistin. While colistin resistance is generally associated with a fitness cost that hinders transmission, this cost was mitigated in a sublineage that had previously acquired mutations increasing its association with patient populations more likely to receive colistin, suggesting a key role for historical contingency in the emergence and spread of stable resistance.</jats:sec

Defining pheromone-receptor signaling in Candida albicans and related asexual Candida species

The pheromone response in Candida albicans is mediated by the Ste2 receptor. Intracellular (IC) loop 3 and C-terminal tail regions of Ste2 are required for signaling, whereas the large IC1 region is dispensable. Heterologous expression of receptors from asexual species can also drive signaling in C. albicans, allowing functional pheromone-receptor couples to be analyzed

Successful Treatment of a Patient with Primary Sjogren\u27s Syndrome Complicated with Pericarditis during Pregnancy

A 35-year-old woman with primary Sjogren\u27s syndrome (pSS) developed fever and chest pain during pregnancy. When the dose of prednisolone was reduced, she experienced chest pain with elevated CRP and D-dimer, resulting in admission to our hospital with marked cardiomegaly and pleural effusion. Because there was no evidence of other autoimmune disorders or infection, oral prednisolone was increased to 30 mg daily with heparin, and hypercoagulopathy was carefully monitored. The patient\u27s condition improved rapidly, and she delivered a healthy baby. This is the first case to support the beneficial effect of prednisolone in pericarditis with pSS, and illustrates its safety during pregnancy

The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation

Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies