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Scientists Sequence Klebsiella Strain Resistant to All Known Antibiotics

Thursday, October 22, 2015

NSRA new publication reports the discovery and analysis of a nightmare bacterium that’s genetically resistant to all commercially available classes of antibiotics.

The paper, “Stepwise evolution of pandrug-resistance in Klebsiella pneumonia,” came out this month in Scientific Reports from Nature. Lead authors Hosam Zowawi and Brian Forde, along with senior author David Paterson and several collaborators, studied an isolate recovered from the urine of an 87-year-old patient who was hospitalized in the United Arab Emirates last year. They used SMRT Sequencing to characterize the strain and its genetic mechanisms for drug resistance.

That strain, MS6671, “was found to be non-susceptible to all antibiotics tested, which includes cephalosporins, penicillins, carbapenems, aztreonam, aminoglycosides, ciprofloxacin, colistin, tetracyclines, tigecycline, chloramphenicol, trimethoprim-sulfamethoxazole and fosfomycin,” the authors report. They note that carbapenem-resistant Enterobacteriaceae (CRE), including Klebsiella and E. coli, are lethal in almost half of patients with bloodstream infections. “The ‘golden era’ when modern medicine saved lives through antibiotic treatment is under serious threat,” they add.

The scientists sequenced the isolate with the PacBio RS II system and performed de novo genome assembly using HGAP and Quiver. The genome includes a circular chromosome about 5.5 Mb long, as well as five circular plasmids and a linear plasmid prophage, the team reports. The circular chromosome is similar to that of a strain of Klebsiella known for its hypervirulence.

Assembly in hand, the team sought the genetic basis for the strain’s broad resistance to antibiotics. They detected a number of acquired antibiotic resistance genes, a novel variant of a gene that appears to confer heightened resistance to carbapanems, and repeated insertions of mobile elements linked to resistance to colistin, an antibiotic used as a last resort. “Our findings provide the first description of pandrug-resistant CRE at the genomic level, and reveal the critical role of mobile resistance elements in accelerating the emergence of resistance to other last resort antibiotics,” the scientists write. According to the paper, this is the first time that anyone has demonstrated resistance to colistin due to the insertion of a carbapanem-resistant mobile element. The authors attribute that partly to SMRT Sequencing, which can accurately sequence complex resistance elements that would confound short-read sequencers.

“Critically, elucidation of the complete K. pneumoniae MS6671 genome using long-read sequencing enabled the context of multiple, identical carbapenem resistance elements to be determined,” the team reports. “Based on this analysis we propose a model for the development of pandrug-resistance in this K. pneumoniae isolate, whereby mobile resistance determinants are responsible for driving additional resistance.”

Zowawi et al. report that as of six months after the patient’s hospitalization, no other cases of this strain had been detected at the facility. “However, the occurrence of this strain in the Arabian Gulf is of great significance,” they write, noting that travel from the region to India, Europe, and the US is common. “The potential for international transfer of multidrug-resistant bacteria emphasizes the need for global surveillance efforts as one part of a strategy to control antibiotic resistance.”

Carbapanem-resistant bacteria have already been cited by health authorities as an urgent threat against human health. “The emergence of this highly resistant strain, in a clone that has proven capable of causing outbreaks, raises this threat level even higher,” the authors conclude.

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