Selective Antibacterials Agent for Multidrug-Resistant Acinetobacter Baumannii
Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most difficult Gram-negative bacteria to treat and eradicate. It cause a variety of diseases, ranging from pneumonia to serious blood infections, and affects people with compromised immune systems.
A. baumannii infections are commonly implicated in hospital-acquired infections, and represent a costly challenge for ICUs in many hospitals.
Mortality rates from A. baumannii septicemia are 34.0−43.4% in the ICU and 16.3% outside the ICU, which is largely attributed to the rise in MDR strains, limiting the treatment options significantly. Currently used agents have broad spectrum activity and are potent inducers of multidrug resistance in bacteria.
Therefore core requirements for a new agent are selectivity for A. Baumannii and activity against MDR strains.
The novel class of pleuromutilin derived antibacterials we developed showed significant synergistic effects with doxycycline against A. baumannii. A combination treatment with doxycycline proofed to be very effective in an in vivo lethal infection model.
Combinations of the current lead 1 and Dox at a series of concentrations exhibit bactericidal activity against drug-sensitive and drug–resistant A. baumannii. A combination treatment of 1-Dox = 35/1 delivered a MIC = 1.56−6.25 μg/mL with an ED50 value of <2 mg/kg (a single dose). The in vivo efficacy of 1-Dox 35/1 was demonstrated via a mouse septicemia model using the infected C57BL/6 mice with A. baumannii. The in vitro bactericidal activity of 1-Dox 35/1 against A. baumannii is superior to that of clinically utilized drugs such as tobramycin, tigecycline, and colistin.
Early pharmacological data included good in vitro half-life (t1/2 > 60 min) in rat microsomes, low in vitro cytotoxicity against mammalian Vero cells (IC50 = 45.3 μg/mL), good permeability across Caco-2 epithelial monolayers with moderate levels of efflux, and a PPB of 76.9%.
The positive activity and pharmacological data we obtained suggest a lower development risk and higher chance to identify a successful candidate to move forward.
- The combination of the lead structure with doxycycline is very effective in vivo even at a single dose.
- Good metabolic stability and early in-vitro PK and toxicity properties. No cytotoxicity against mammalian cell lines at 40 µg/mL concentrations (IC50 50-100 µg/mL).
- Straightforward scalable synthesis and derivatization.
- J. Med. Chem., 2017, 60 (7), pp 2869–2878
- Provisional patent application filed February 2017.