Apramycin scaffold exploration using novel glycochemistry and SAR studies to enhance activity against Acinetobacter baumannii and other multidrug-resistant Gram-negative pathogens.
KP Smith Speaking tomorrow at Harvard Antimicrobial Resistance Laboratory Network as well as Broad Institute collaborator, Alejandro Pironti
Evaluation of apramycin activity against methicillin-resistant, methicillin-sensitive, and vancomycin-intermediate Staphylococcus aureus clinical isolates. Now online, congrats to Kat Truelson, see previous post.
BIDMC news release on Thea's antimicrobial synergy paper:
"Bacteria—especially Gram-negative strains—are becoming increasingly resistant to current antibiotic drugs, and the development of new classes of antibiotics has slowed. Faced with these challenges, investigators are studying the potential of combination therapy, in which two or more drugs are used together to increase or restore the efficacy of both drugs against a resistant bacterial pathogen. Now new research indicates that such synergy may work even when bacteria become resistant to colistin, which is considered a treatment agent of last resort.
The findings are especially promising because recent evidence indicates the potential for rapid worldwide spread of colistin resistance. “For an infected patient, if the multidrug-resistant Gram-negative bacterial pathogen is resistant to colistin, then there is a big problem,” said senior author James Kirby, MD, Director of the Clinical Microbiology Laboratory at BIDMC.
In their Antimicrobial Agents and Chemotherapy study, Kirby and his colleagues Thea Brennan-Krohn, MD and Alejandro Pironti, PhD screened 19 different antibiotics for synergy with colistin. The team discovered several combinations where synergy was present and infections with resistant pathogens could potentially be treated with the combination therapy.
Of particular interest, colistin demonstrated high rates of synergy with linezolid, fusidic acid, and clindamycin, which are protein synthesis inhibitor antibiotics that individually have no activity against Gram-negative bacteria. “It was remarkable to see two drugs, each of which is inactive on its own against these bacteria, inhibiting them in combination,” notes Brennan-Krohn. “These findings suggest that colistin retains sub-lethal activity against colistin-resistant bacteria, which may enable drugs like linezolid to reach their targets.”
“Faced with highly resistant pathogens, clinicians often currently treat with multiple antibiotics without knowing the benefit the combinations may provide,” said Kirby. “This study now provides some scientific underpinning for these choices and direction for future investigation.” He added that combination therapy may also allow clinicians to use lower effective doses of colistin and other drugs, which would help avoid toxicities associated with the medications as well as slow the development of antibiotic resistance.
This work was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and the Department of Health and Human Services."
"But it must be said that we have failed in controlling antimicrobial resistance whenever a physician has to make a choice between a safe drug that might not work and a dangerous but effective one." (page 38-39).
Congratulations to Kat Truelson on her publication in DMID on apramycin activity against contemporary multidrug-resistant strains of Staphylococcus aureus
Kat had a very productive undergraduate experience in the laboratory while attending Boston University as an undergraduate. Her first author manuscript titled: "Evaluation of Apramycin Activity Against Methicillin-Resistant, Methicillin-Sensitive, and Vancomycin-Intermediate Staphylococcus aureus Clinical Isolates" was just accepted into Diagnostic Microbiology and Infectious Diseases, more commonly referred to as DMID. Congratulations! She found that apramycin was equally active against MSSA, MRSA, and VISA strains, and demonstrated rapid time-kill kinetics. This manuscript expands apramycin's known activity spectrum to include contemporaneous human clinical strains of multidrug-resistant carbapenem=resistant Enterobacteriaceae = CRE; Acinetobacter baumannii, and Pseudomonas aeruginosa, and now Staphylococcus aureus.
We are very excited for Kat as she is moving this summer to the University of Chicago to work on a much beloved organism, Legionella pneumophila, in Howard Shuman's laboratory.
"The Inoculum Effect in the Era of Multidrug Resistance: Minor Differences in Inoculum Have Dramatic Effect on Minimal Inhibitory Concentration Determination."
The manuscript describes use of D300-based inkjet printing technology to investigate the inoculum effect with a resolution not previously possible. The inoculum effect is the general observation that the minimal inhibitor concentration (in other words level of resistance) of an organism to an antibiotic increases when a higher density of organisms is tested. This is effect is especially prominent for beta-lactam antiibiotics. It is of potential clinical concern during some types of infections when the organism burden is high. Here we explored whether subtle differences in inoculum within the range allowed by current standards can effect the susceptibility testing results that clinical laboratories obtain and provide to clinicians. Our findings for organisms with certain types of multidrug-resistance and very important classes of antibiotics was that these small allowable differences in inoculum could change the MIC determinations and the determination of whether organisms were susceptible or resistant to the antibiotics tested.
KP Smith wins an "Outstanding Abstract Award" otherwise known as the OAA, for his experimental work on the inoculum effect.
The award description on the ASM Microbe 2018 awards website: "Sponsored by ASM and determined by the ASM Microbe Program Committee, these awards highlight outstanding abstracts presented by students, residents, or medical/clinical fellows. All abstracts submitted by the deadline will be considered for these awards. Awards will include a cash prize of $200."
Congratulations to lab members, Anthony Kang, and colleagues for our manuscript newly accepted in Antimicrobial Agents and Chemotherapy titled: "Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model"
The manuscripts describes potent in vitro and in vivo activity of the apramycin, an aminocyclitol aminoglycoside, against multidrug-resistant and extensively-drug resistant Acinetobacter baumannii.
In prior manuscripts, we demonstrated broad activity against several types of multidrug-resistant pathogens including carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii and Pseudomonas aeruginosa
Kirby Lab Blog