Repurposing clinically approved cephalosporins for tuberculosis therapy.
While modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (TB) therapy, we identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. Common chemical patterns required for activity against Mycobacterium tuberculosis were identified using structure-activity relationships (SAR) studies. Numerous cephalosporins were synergistic with rifampicin, the cornerstone drug for TB therapy, and ethambutol, a first-line anti-TB drug. Synergy was observed even under intracellular growth conditions where beta-lactams typically have limited activities. Cephalosporins and rifampicin were 4- to 64-fold more active in combination than either drug alone; however, limited synergy was observed with rifapentine or rifabutin. Clavulanate was a key synergistic partner in triple combinations. Cephalosporins (and other beta-lactams) together with clavulanate rescued the activity of rifampicin against a rifampicin resistant strain. Synergy was not due exclusively to increased rifampicin accumulation within the mycobacterial cells. Cephalosporins were also synergistic with new anti-TB drugs such as bedaquiline and delamanid. Studies will be needed to validate their in vivo activities. However, the fact that cephalosporins are orally bioavailable with good safety profiles, together with their anti-mycobacterial activities reported here, suggest that they could be repurposed within new combinatorial TB therapies.
Department of Microbiology and Immunology, Centre for Tuberculosis Research, Life Sciences Centre, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada.|GlaxoSmithKline-Diseases of the Developing World, Tres Cantos, Madrid, Spain.
Santiago
S
Ramón-García
GlaxoSmithKline-Diseases of the Developing World, Tres Cantos, Madrid, Spain.
Rubén
R
González Del Río
GlaxoSmithKline-Diseases of the Developing World, Tres Cantos, Madrid, Spain.
Angel Santos
AS
Villarejo
Department of Microbiology and Immunology, Centre for Tuberculosis Research, Life Sciences Centre, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada.
Gaye D
GD
Sweet
GlaxoSmithKline-Diseases of the Developing World, Tres Cantos, Madrid, Spain.
Fraser
F
Cunningham
GlaxoSmithKline-Diseases of the Developing World, Tres Cantos, Madrid, Spain.
David
D
Barros
GlaxoSmithKline-Diseases of the Developing World, Tres Cantos, Madrid, Spain.
Lluís
L
Ballell
GlaxoSmithKline-Diseases of the Developing World, Tres Cantos, Madrid, Spain.
Alfonso
A
Mendoza-Losana
GlaxoSmithKline-Diseases of the Developing World, Tres Cantos, Madrid, Spain.
Santiago
S
Ferrer-Bazaga
Department of Microbiology and Immunology, Centre for Tuberculosis Research, Life Sciences Centre, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada.
Charles J
CJ
Thompson
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