Repurposing clinically approved cephalosporins for tuberculosis therapy
Background. While modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (TB) therapy, we explored their potential repositioning as new anti-TB drugs.
Objectives. We previously demonstrated that combinatorial drug therapy might be employed to increase the efficacies of available antibiotics, allowing them to be repurposed for TB therapy within synergistic combinations [doi: 10.1128/AAC.00474-11]. Rifampicin, the cornerstone drug for TB therapy, is not administered at its optimal clinical dose due to long-established toxicity concerns. If the anti-mycobacterial activity of rifampicin could be increased, TB therapy could be shortened, thus reducing the rate of transmission and the emergence of drug resistance.
Methods. We screened an in-house library of ca. 600 commercially available antibiotics, and found that (i) cephalosporins had strong synergies with rifampicin and ethambutol, a first-line anti-TB drug (4- to 64-fold more active in combination than either drug alone); (ii) common chemical patterns required for single drug activity against Mtb were identified using structure-activity relationships (SAR) studies; (iii) synergy was observed even under intracellular growth conditions where beta-lactams typically have limited activities; (iv) cephalosporins and rifampicin were synergistic but limited synergy was observed with rifapentine or rifabutin; (v) Clavulanate was a key synergistic partner in triple combinations, together with cephalosporins rescued the activity of rifampicin against a rifampicin resistant strain; (vi) uptake experiments demonstrated that synergy was not due exclusively to increased rifampicin accumulation within the mycobacterial cells, and; (vii) cephalosporins were also synergistic with new anti-TB drugs such as bedaquiline and delamanid.
Conclusions. We identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. Cephalosporins are orally bioavailable with good safety profiles; together with their anti-mycobacterial activities reported here, it suggests that they could be repurposed within new combinatorial TB therapies.
For more info see here: doi:10.1038/srep34293.