The activity, mode of action and generation of resistance to novel antibacterial agents

The failure of antibiotics to treat infections caused by multi-drug resistant bacteria is a significant problem in the field of antimicrobial chemotherapy. The characterisation and development of antibacterial agents displaying novel modes of action (MOAs) or the modification of existing antibiotic scaffolds may address this problem. This study therefore sought to identify antibiotic candidates, establishing their antibacterial activity, bacterial specificity, MOA and propensity for resistance development. From nearly half a million compounds which were screened in silica against RNA polymerase (RNAP), D-alanine: D-alanine ligase and peptidoglycan transglycosylases, no inhibitors with specific activity against their target were identified, which highlights the difficulties of developing novel antibacterial agents. However, targeted inhibition of the cell envelope and RNAP were observed for the type B lantibiotic derivative NVB353 and corallopyronin A, respectively. The former may show greater promise as a chemotherapeutic candidate, due to lower propensity for resistance development. In addition, a number of compounds which appear to damage the bacterial cell membrane specifically were identified, and which may be suitable for treatment of persistent bacterial infections. Transcriptional profiling of Staphylococcus aureus treated with a panel of known membrane damagers was also used to identify upregulafed genes which might be potential candidates for future development of biosensors solely responsive to membrane damage. These biosensors could be used to eliminate compounds which are likely to cause non-specific toxic side effects if administered to humans, but may also identify membrane damaging agents that could be developed for clinical use should they show bacterial specificity.