Abstract
PurposeThe emergence of bacteria that are resistant to many currently used drugs emphasizes the need to discover and develop new antibiotics that are effective against such multi-resistant strains. Kendomycin is a novel polyketide that has a unique quinone methide ansa structure and various biological properties. This compound exhibits strong antibacterial activity against Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Despite the promise of kendomycinin in several therapeutic areas, its mode of action has yet to be identified.MethodsIn this study, we used a multidisciplinary approach to gain insight into the antibacterial mechanism of this compound.ResultsThe antibacterial activity of kendomycin appears to be bacteriostatic rather than bactericidal. Kendomycin inhibited the growth of the MRSA strain COL at a low concentration (MIC of 5 μg/mL). Proteomic analysis and gene transcription profiling of kendomycin-treated cells indicated that this compound affected the regulation of numerous proteins and genes involved in central metabolic pathways, such as the tricarboxylic acid (TCA) cycle (SdhA) and gluconeogenesis (PckA and GapB), cell wall biosynthesis and cell division (FtsA, FtsZ, and MurAA), capsule production (Cap5A and Cap5C), bacterial programmed cell death (LrgA and CidA), the cellular stress response (ClpB, ClpC, ClpP, GroEL, DnaK, and GrpE), and oxidative stress (AhpC and KatA). Electron microscopy revealed that kendomycin strongly affected septum formation during cell division. Most kendomycin-treated cells displayed incomplete septa with abnormal morphology.ConclusionsKendomycin might directly or indirectly affect the cell division machinery, protein stability, and programmed cell death in S. aureus. Additional studies are still needed to obtain deeper insight into the mode of action of kendomycin.
Highlights
Natural products remain a primary source of therapeutic drugs [1,2,3,4,5,6,7,8,9,10,11] and are valuable tools for investigating and modulating cell biology
Kendomycin inhibited the growth of the methicillin-resistant Staphylococcus aureus (MRSA) strain COL at a low concentration (MIC of 5 μg/mL)
Proteomic analysis and gene transcription profiling of kendomycin-treated cells indicated that this compound affected the regulation of numerous proteins and genes involved in central metabolic pathways, such as the tricarboxylic acid (TCA) cycle (SdhA) and gluconeogenesis (PckA and GapB), cell wall biosynthesis and cell division (FtsA, FtsZ, and MurAA), capsule production (Cap5A and Cap5C), bacterial programmed cell death (LrgA and CidA), the cellular stress response (ClpB, ClpC, ClpP, GroEL, DnaK, and GrpE), and oxidative stress (AhpC and kendomycin treatment included catalase (KatA))
Summary
Natural products remain a primary source of therapeutic drugs [1,2,3,4,5,6,7,8,9,10,11] and are valuable tools for investigating and modulating cell biology For these compounds to be effective tools, their modes of action and their molecular interactions with corresponding cellular target (s) must be understood. S. aureus is a common cause of hospital- and community-acquired infections [18,19,20] This Gram-positive bacterium colonizes the anterior nares of at least one-third of the human population and causes a variety of infections ranging from simple wound infections to severe systematic infections, such as pneumonia and osteomyelitis. The pathogenicity of this organism is believed to depend largely on its ability to adapt to various host niches and to coordinate the expression of its large reservoir of virulence factors [21,22]
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