8-Hydroxyquinoline Series Exerts Bactericidal Activity against Via Copper-Mediated Toxicity.

New drugs and mechanisms of action targeting are urgently needed to solve the global pandemic of tuberculosis. We previously demonstrated that the 8-hydroxyquinoline series has rapid bactericidal activity against . In this work, we determined that the activity of the 8HQ series is potentiated by copper ions and that the activity is dependent on copper since activity was reduced when copper was depleted from the medium.

MSMEG_0918 is not Essential for the Growth of .

Copper homeostasis plays a crucial role in mycobacteria. In , Rv0474 is a copper-responsive regulator with a copper-binding motif but its homolog in , MSMEG_0918, lacks the copper-binding motif. We generated MSMEG_0918 knockdown strains of using CRISPRi.

How drug resistance has shaped anti-tubercular drug discovery.

Drug resistance is an increasing problem for the treatment of tuberculosis. The prevalence of clinical isolates with pre-existing resistance needs to be considered in any drug discovery program. Non-specific mechanisms of resistance such as increased efflux or decreased permeability need to be considered both in developing individual drug candidates and when designing novel regimens.

Influence of bacterial culture medium on peptidoglycan binding of cell wall lytic enzymes.

The bacteriolysin lysostaphin (Lst) and endolysin PlyPH are potent modular lytic enzymes with activity against clinically-relevant Gram-positive Staphylococcus aureus and Bacillus cereus, respectively. Both enzymes possess an N-terminal catalytic domain and C-terminal binding domain, with the latter conferring significant enzyme specificity. Lst and PlyPH show reduced activity in the presence of bacterial growth-supporting conditions, such as complex media.

Opportunities for broadening the application of cell wall lytic enzymes.

In light of emerging antibiotic resistance, bacterial cell wall lytic enzymes are promising antimicrobial agents that degrade bacterial peptidoglycan while specifically recognizing the target bacterium. The efficacy of lytic enzymes against several multi-drug-resistant pathogens infecting humans has led to many efforts focused on in vivo therapeutic applications. However, the potential for lytic enzymes to combat bacterial contamination in environments outside the human body is underexplored.

Selective antimicrobial activity of cell lytic enzymes in a bacterial consortium.

The role that the complex microbial communities play in human and environmental health cannot be understated. The increased information about community complexity, as well as the overuse of broad-spectrum antibiotics, suggest that new approaches to target specific organisms within a community context are essential towards new antimicrobial therapies. Here, we have assessed the activity and selectivity of two cell wall lytic enzymes, lysostaphin (Lst) and PlyPH, in the presence of multiple bacteria and under varied media conditions.