Discovery of kibdelomycin, a potent new class of bacterial type II topoisomerase inhibitor by chemical-genetic profiling in Staphylococcus aureus.

Bacterial resistance to known therapeutics has led to an urgent need for new chemical classes of antibacterial agents. To address this we have applied a Staphylococcus aureus fitness test strategy to natural products screening. Here we report the discovery of kibdelomycin, a novel class of antibiotics produced by a new member of the genus Kibdelosporangium. Kibdelomycin exhibits broad-spectrum, gram-positive antibacterial activity and is a potent inhibitor of DNA synthesis. We demonstrate through chemical genetic fitness test profiling and biochemical enzyme assays that kibdelomycin is a structurally new class of bacterial type II topoisomerase inhibitor preferentially inhibiting the ATPase activity of DNA gyrase and topoisomerase IV. Kibdelomycin is thus the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades.

Antibacterial evaluations of thiazomycin- a potent thiazolyl peptide antibiotic from Amycolatopsis fastidiosa.

Thiazomycin is a novel thiazolyl peptide closely related to nocathiacin I. It was isolated from Amycolatopsis fastidiosa by chemical and biological screening. Thiazomycin showed highly potent bactericidal activity against Gram-positive pathogens (MIC range 0.002 approximately 0.064 microg/ml) and did not show cross-resistance to clinically relevant antibiotic classes such as beta-lactams, vancomycin, oxazolidinone and quinolones. It was highly efficacious against Staphylococcus aureus infection in mice exhibiting an ED(99) value of 0.15 mg/kg by subcutaneous administration. It inhibited bacterial growth by selective inhibition of protein synthesis and it was thought to interact with L11 protein and 23S rRNA of the 50S ribosome. Structurally, it possesses an oxazolidine ring in the amino-sugar residue that provides further opportunities for selective chemical modifications that are not feasible with other thiazolyl peptides. More importantly such a modification can potentially lead to semi-synthetic compounds that overcome problems that have hampered clinical development of this class of compounds. Despite its positive attributes, emergence of an unacceptable frequency of resistance poses significant challenges for further development of thiazomycin and this class of molecules for therapeutic use.

Antibiotics: where did we go wrong?

In the late 1960s, the medical need for new antibiotics began to be questioned, and the pharmaceutical industry shifted its emphasis of antibacterials from that of a therapeutic leader to a low-priority research area. Although infectious diseases, in particular those caused by bacterial infections, are still among the top causes of mortality in the world, industrial support continues to wane. The shift from this important area of antimicrobial research has been attributed to a combination of science, medical, marketing and business reasons. This decline in antibacterial drug discovery, coupled with increasing risk as a result of infections caused by drug-resistant bacterial pathogens, represents a clear public health threat.

Real-time monitoring of bacterial infection in vivo: development of bioluminescent staphylococcal foreign-body and deep-thigh-wound mouse infection models.

Staphylococcal infections associated with catheter and prosthetic implants are difficult to eradicate and often lead to chronic infections. Development of novel antibacterial therapies requires simple, reliable, and relevant models for infection. Using bioluminescent Staphylococcus aureus, we have adapted the existing foreign-body and deep-wound mouse models of staphylococcal infection to allow real-time monitoring of the bacterial colonization of catheters or tissues. This approach also enables kinetic measurements of bacterial growth and clearance in each infected animal. Persistence of infection was observed throughout the course of the study until termination of the experiment at day 16 in a deep-wound model and day 21 in the foreign-body model, providing sufficient time to test the effects of antibacterial compounds. The usefulness of both animal models was assessed by using linezolid as a test compound and comparing bioluminescent measurements to bacterial counts. In the foreign-body model, a three-dose antibiotic regimen (2, 5, and 24 h after infection) resulted in a decrease in both luminescence and bacterial counts recovered from the implant compared to those of the mock-treated infected mice. In addition, linezolid treatment prevented the formation of subcutaneous abscesses, although it did not completely resolve the infection. In the thigh model, the same treatment regimen resulted in complete resolution of the luminescent signal, which correlated with clearance of the bacteria from the thighs.