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Activation of multiple stress responses in Staphylococcus aureus substantially lowers the MIC when combining two novel antibiotic drug candidates

ABSTRACT: The past few decades have been plagued by an increasing number of infections caused by antibiotic resistant bacteria. To mitigate the rise in untreatable infections, we need new antibiotics with novel targets and drug combinations that reduce resistance development. The novel β-clamp targeting antimicrobial peptide BTP-001 was recently shown to have a strong additive effect in combination with the halogenated pyrrolopyrimidine JK-274. In this study, the molecular basis for this effect was examined by a comprehensive proteomic and metabolomic study of the individual and combined effects on Staphylococcus aureus. We found that JK-274 reduced activation of several TCA cycle enzymes, likely via increasing the cellular nitric oxide stress, and BTP-001 induced oxidative stress in addition to inhibiting replication, translation, and DNA repair processes. Analysis indicated that several proteins linked to stress were only activated in the combination and not in the single treatments. These results suggest that the strong additive effect is due to the activation of multiple stress responses that can only be trigged by the combined effect of the individual mechanisms. Importantly, the combination dose required to eradicate S. aureus was well tolerated and did not affect cell viability of immortalized human keratinocyte cells. Our findings demonstrate the potential of JK-274 and BTP-001 as antibiotic drug candidates and warrant further studies.

INSTRUMENT(S): Bruker Daltonics timsTOF series

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Amanda Singleton

LAB HEAD: Marit Otterlei

PROVIDER: PXD043757 | Pride | 2023-09-13

REPOSITORIES: Pride

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Project description:Estrogen receptor positive breast cancer is the most prevalent form of breast cancer. Although a number of available drugs are highly effective at blocking estrogen mediated receptor activity, thousands of patients die every year from ER positive breast cancers because the disease progresses to a stage at which these drugs are no longer effective. Thus, it is crucial to establish a comprehensive understanding of the biology of the estrogen receptor (ER) in ER:positive breast cancers that progress despite hormone therapy, a gap in knowledge that remains a serious impediment to successful treatment of patients with ER positive breast cancer. A key question that must be answered is how the estrogen receptor retains the capacity to activate transcription in the absence or near absence of estrogen. We have found a partial answer to this question upon investigating the effect of amplification and overexpression of Wolf Hirschhorn Syndrome Candidate 1:Like 1 (WHSC1L1), a gene that is amplified in 15% of breast cancers that codes for a histone:lysine methyltransferase. WHSC1L1 lies in the 8p11:p12 amplicon, a region of gene amplification that is strongly associated with breast cancer. In this study, we performed shRNA knockdown of the catalytically inactive short isoform of WHSC1L1 in SUM44PE breast cancer cells and found that expression of the short isoform of WHSC1L1 is necessary for expression of the estrogen receptor in this highly ER:positive cell line. In addition, we found that the estrogen receptor binds chromatin extensively in the absence of exogenous estrogen, including several actively transcribed canonical ER target genes, indicating that estrogen receptor signaling is active in SUM44 cells in estrogen free conditions. These findings represent a novel model for ER biology in luminal B breast cancers harboring amplification of WHSC1L1 and provide insight into the mechanisms by which ER: positive breast cancers become unresponsive to SERMs or aromatase inhibitors.

			Action	DRS
	Deamidation_NQ_Sites.txt	Txt
	Oxidation_M_Sites.txt	Txt
	Raw_data.zip	Other
	Sample_groups.txt	Txt
	Tables.pdf	Pdf

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Activation of multiple stress responses in Staphylococcus aureus substantially lowers the MIC when combining two novel antibiotic drug candidates

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