RT Journal Article
T1 Repurposing clinically approved cephalosporins for tuberculosis therapy
A1 Ramón García, Santiago
A1 González Del Río, Rubén
A1 Santos Villarejo, Ángel
A1 D. Sweet, Gaye
A1 Cunningham, Fraser
A1 Barros, David
A1 Ballell, Lluis
A1 Mendoza Losana, Alfonso
A1 Ferrer Bazaga, Santiago
A1 J. Thompson, Charles
AB 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.
PB Springer
SN 2045-2322
YR 2016
FD 2016-09-28
LK https://hdl.handle.net/10016/38872
UL https://hdl.handle.net/10016/38872
LA eng
NO This work was supported by grants from the British Columbia Lung Association and The Canadian Institute of Health Research (MOP-82855) to C.J.T. and from a Grand Challenges Canada - Stars in Global Health (0030-01-04-01-01) and a People Programme (Marie Skłodowska Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA agreement no. 291799 (Tres Cantos Open Lab Foundation - COFUND programme) to S.R.-G.
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RD 1 jun. 2024