Carbapenem-resistant Enterobacteriaceae (CRE)
Klebsiella pneumoniae
Klebsiella pneumoniae are a cause of urinary tract, bloodstream, lung, and tissue infection. Alarmingly, multidrug-resistance is emerging at a rapid pace in this genus due to acquisition of large plasmids encoding a plethora of resistance elements. Epidemiologically, two emerging resistance mechanisms in the United States are especially notable -- those encoding extended spectrum beta-lactamases, so called ESBL, and those encoding Klebsiella pneumonia carbapemases, also known as KPC elements. The former generally confer resistance to all penicillins and all generations of cephalosporins. The latter confer resistance to penicillins, cephalosporins, and carbapenems (meropenem, imipenem, ertapenem). Resistance plasmids typically encode not only ESBL and KPC genes but also elements conferring resistance to multiple additional classes of antimicrobials such as aminoglycosides (gentamicin, amikacin, tobramycin) and, cause for some alarm, colistin, an agent of potential last resort for treatment of CRE and other multidrug-resistant Gram-negative pathogens.
Klebsiella are part of the flora colonizing the intestines. Intestinal colonization with multidrug-resistant species is of special concern, as this colonization forms the internal reservoir of pathogens that are the future agents of clinical infection in the same host. Patients who are treated with antibiotics are at greatly increased risk for colonization, since normal antibiotic-sensitive flora is wiped out and multidrug-resistant pathogens are free to colonize in their place. Therefore, the sickest patients, often treated with prolonged courses of antibiotics, are at greatest risk for colonization and subsequent devastating infection with these multidrug-resistant organisms.
KP Smith, a postdoctoral fellow in the Kirby laboratory, recently described a validation of a high throughput screening strategy to identify small molecules that either directly inhibit CRE or potentiate the activity of meropenem against CRE. Interestingly, several existing human drugs (AZT, spectinomycin, apramycin) showed excellent activity, with fairly broad activity spectrum against a large panel of highly resistant CRE strains tested. These and related agents warrant further study. They potentially could be repurposed for treatment of CRE and other multidrug-resistant pathogens (Pseudomonas aeruginosa and Acinetobacter baumannii) or serve as the starting points for medicinal chemistry to seek derivatives with more favorable activity profiles. We are collaborating with the medicinal chemistry group of Roman Manetsch at Northeastern University to further explore compound "scaffolds" identified through our high throughput screening efforts and our review of the natural product literature with promising activity against CRE.
Klebsiella are part of the flora colonizing the intestines. Intestinal colonization with multidrug-resistant species is of special concern, as this colonization forms the internal reservoir of pathogens that are the future agents of clinical infection in the same host. Patients who are treated with antibiotics are at greatly increased risk for colonization, since normal antibiotic-sensitive flora is wiped out and multidrug-resistant pathogens are free to colonize in their place. Therefore, the sickest patients, often treated with prolonged courses of antibiotics, are at greatest risk for colonization and subsequent devastating infection with these multidrug-resistant organisms.
KP Smith, a postdoctoral fellow in the Kirby laboratory, recently described a validation of a high throughput screening strategy to identify small molecules that either directly inhibit CRE or potentiate the activity of meropenem against CRE. Interestingly, several existing human drugs (AZT, spectinomycin, apramycin) showed excellent activity, with fairly broad activity spectrum against a large panel of highly resistant CRE strains tested. These and related agents warrant further study. They potentially could be repurposed for treatment of CRE and other multidrug-resistant pathogens (Pseudomonas aeruginosa and Acinetobacter baumannii) or serve as the starting points for medicinal chemistry to seek derivatives with more favorable activity profiles. We are collaborating with the medicinal chemistry group of Roman Manetsch at Northeastern University to further explore compound "scaffolds" identified through our high throughput screening efforts and our review of the natural product literature with promising activity against CRE.
Escherichia coli
Escherichia coli is the most frequent cause of urinary tract infection, Gram-negative bloodstream infection, and sepsis. As for Klebsiella sp., Escherichia coli are part of the normal flora colonizing the intestines, and colonization (within multi-drug resistant strains) precedes infection. Acquisition of ESBL and KPC elements by this organism is also increasingly common. A fluoroquinolone (e.g., ciprofloxacin, levofloxacin, moxifloxacin) resistant clone is emerging in the US, known as sequence type 131 (ST-131). This emerging strain is also commonly resistant to trimethoprim/sulfamethoxazole (brand name Bactrim), making empiric treatment of urinary tract infections and prophylactic treatment prior to bowel perforating procedures (e.g., prostate biopsy) problematic. Of concern, ST-131 strains can also acquire ESBL or KPC elements making them highly resistant.
Enterobacter sp.
Enterobacter sp. are yet another member of the Enterobacteriaceae that cause clinical significant multi-drug resistant infections and live in the intestines. Most clinical strains of Enterobacter (e.g., E. aerogenes, E. cloacea) already contain an inducible, broad-spectrum β-lactamase known as AmpC that confers resistance to penicillins; and first, second, and third generation cephalosporins. However, many clinical strains through selection have become permanently derepressed and constitutively express this resistance element . Enterobacter may further acquire ESBL, KPC, and NDM-1 expressing plasmids, broadening their resistance to include fourth generation cephalosporins and carbapenems.
CRE Therapeutics
We review CRE therapeutic options. Also see Figures for structures of current and future CRE therapeutic option. Final accepted manuscript:
"New Strategies and Structural Considerations in Development of Therapeutics for Carbapenem-Resistant Enterobacteriaceae: New Therapies for CRE"
"New Strategies and Structural Considerations in Development of Therapeutics for Carbapenem-Resistant Enterobacteriaceae: New Therapies for CRE"
CRE Genomics
A recent genomics study, including many strains from our institution, highlights the idea that CRE are spreading in the community. Mysteriously, CRE infection in the Boston area remains relatively low compared to other areas in the United States. NDM-1 producing strains (New Delhi Metallo-beta-lactamase-1) are as of yet relatively rare in the United States.. However, emerging pandrug-resistant NDM-1 CRE strains are of great concern and provides significant impetus to our antimicrobial drug discovery work.