Discovery of Novel First-in-Class Small Molecules for the Treatment of Multidrug Resistant bacteria

T.H. Al-Tel, R. El‐Awady, V. Srinivasulu, F. Ibrahim Al‐Marzooq
University of Sharjah, United Arab Emirates

Keywords: methicillin-resistant Staphylococcus aureus, first-in-class novel small molecules, multidrug resistant bacteria

We have discovered first-in-class small molecules that are active against multidrug resistant Staphylococcus, especially on MRSA. Some compounds were found to be 10-20 times more potent than ciprofloxacin when tested against several species of Staphylococcus bacteria. For example, compounds SIMR-1391 and 1458 possess minimum inhibitory concentration (MIC) of 3.125 ug/ml against a strain of S. saprophyticus compared to 125 ug/ml for ciprofloxacin. These compounds were found to be effective in preventing biofilm formation by the resistant bacteria. For example, compounds SIMR-1391 and 1458 possess minimum biofilm inhibitory concentration of 12.5 ug/ml against a strain of S. saprophyticus which is equal to that of meropenem (12.5 ug/ml). We found that MRSA bacteria were not able to develop single step spontaneous resistant mutants against our compounds. Furthermore, the discovered compounds were able to kill the bacteria at a very fast rate (30 minutes) compared to known antibiotics (24 hours). Imaging of the bacteria exposed to the compounds under AFM revealed bacterial cell wall distortion and leakage of the intracellular contents, due to the lytic effect of the compounds. When testing the compounds against normal cells and red blood cells, the compounds were found to be safe even at high concentration (10uM).