There is an enormous global public health burden due to antimicrobial resistance (AMR) Klebsiella pneumoniae high-risk clones. K. pneumoniae ST307 and ST147 are recent additions to the family of successful clones among these species. Both clones likely emerged in Europe during the early to mid-1990s, and in a relatively short time, became prominent global pathogens, spreading to all continents (with the exception of Antarctica). ST307 and ST147 consist of multiple clades/clusters respectively and are associated with various carbapenemases (i.e. KPCs, NDMs, OXA-48-like and VIMs). ST307 is endemic in Italy, Colombia, USA (Texas), and South Africa, while ST147 is endemic in India, Italy, Greece and certain North African countries. Both clones have been introduced into non-endemic regions leading to world-wide nosocomial outbreaks. Genomic studies showed ST307 and ST147 contain identical gyrA and parC mutations and likely obtained plasmids with bla_CTX-M-15 during the early to mid-2000s, which aided in their global distribution. ST307 and ST147 then acquired plasmids with various carbapenemases during the late 2000s, establishing themselves as important AMR pathogens in certain regions. Both clones are likely underreported due to restricted detection methodologies. ST307 and ST147 have the ability to become major threats to public health due to their worldwide distribution, ability to cause serious infections and association with AMR including pan-resistance. The medical community at large, especially those concerned with antimicrobial resistance, should be aware of the looming threat posed by emerging AMR high-risk clones such as K. pneumoniae ST307 and ST147.

Klebsiella pneumoniae has been classified into two types, classical K. pneumoniae (cKP) and hypervirulent K. pneumoniae (hvKP). cKP isolates are highly diverse and important causes of nosocomial infections; they include globally disseminated antibiotic-resistant clones. hvKP isolates are sensitive to most antibiotics but are highly virulent, causing community-acquired infections in healthy individuals. The virulence phenotype of hvKP is associated with pathogenicity loci responsible for siderophore and hypermucoid capsule production. Recently, convergent strains of K. pneumoniae, which possess features of both cKP and hvKP, have emerged and are cause of much concern. Here, we screen the genomes of 2,608 multidrug-resistant K. pneumoniae isolates from the United States and identify 47 convergent isolates. We perform phenotypic and genomic characterization of 12 representative isolates. These 12 convergent isolates contain a variety of antimicrobial resistance plasmids and virulence plasmids. Most convergent isolates contain aerobactin biosynthesis genes and produce more siderophores than cKP isolates but not more capsule. Unexpectedly, only 1 of the 12 tested convergent isolates has a level of virulence consistent with hvKP isolates in a murine pneumonia model. These findings suggest that additional studies should be performed to clarify whether convergent strains are indeed more virulent than cKP in mouse and human infections.

Escherichia coli ST1193 is an emerging global multidrug (MDR) high-risk clone and an important cause of community-onset urinary and bloodstream infections.

Combating plasmid-mediated carbapenem resistance is essential to control and prevent the dissemination of carbapenem-resistant Enterobacteriaceae (CRE). Here, we conducted a proof-of-concept study to demonstrate that CRISPR-Cas9-mediated resistance gene and plasmid curing can effectively resensitize CRE to carbapenems. A novel CRISPR-Cas9-mediated plasmid-curing system (pCasCure) was developed and electrotransferred into various clinical CRE isolates. The results showed that pCasCure can effectively cure bla _KPC , bla _NDM , and bla _OXA-48 in various Enterobacteriaceae species of Klebsiella pneumoniae , Escherichia coli , Enterobacter hormaechei , Enterobacter xiangfangensis , and Serratia marcescens clinical isolates, with a >94% curing efficiency.

In the face of the alarming rise in global antimicrobial resistance, only a handful of novel antibiotics have been developed in recent decades, necessitating innovations in therapeutic strategies to fill the void of antibiotic discovery. Here, we established a screening platform mimicking the host milieu to select antibiotic adjuvants and found three catechol-type flavonoids—7,8-dihydroxyflavone, myricetin, and luteolin—prominently potentiating the efficacy of colistin. Further mechanistic analysis demonstrated that these flavonoids are able to disrupt bacterial iron homeostasis through converting ferric iron to ferrous form. The excessive intracellular ferrous iron modulated the membrane charge of bacteria via interfering the two-component system pmrA / pmrB , thereby promoting the colistin binding and subsequent membrane damage. The potentiation of these flavonoids was further confirmed in an in vivo infection model. Collectively, the current study provided three flavonoids as colistin adjuvant to replenish our arsenals for combating bacterial infections and shed the light on the bacterial iron signaling as a promising target for antibacterial therapies.