N-Benzylanilines as Fatty Acid Synthesis Inhibitors against Biofilm-related Methicillin-resistant Staphylococcus aureus

ABSTRACTInactivation of acetyl-coenzyme A (acetyl-CoA) carboxylase confers resistance to fatty acid synthesis inhibitors inStaphylococcus aureuson media supplemented with fatty acids. The addition ofanteiso-fatty acids (1 mM) plus lipoic acid supports normal growth of ΔaccDstrains, but supplementation with mammalian fatty acids was less efficient. Mice infected with strain RN6930 developed bacteremia, but bacteria were not detected in mice infected with its ΔaccDderivative.S. aureusbacteria lacking acetyl-CoA carboxylase can be propagatedin vitrobut were unable to proliferate in mice, suggesting that the acquisition of inactivating mutations in this enzyme is not a mechanism for the evasion of fatty acid synthesis inhibitors.

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Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02515-16 ◽

2017 ◽

Vol 61 (5) ◽

Cited By ~ 14

Author(s):

Karine Gloux ◽

Mélanie Guillemet ◽

Charles Soler ◽

Claire Morvan ◽

David Halpern ◽

...

Keyword(s):

Fatty Acids ◽

Staphylococcus Aureus ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

Bacterial Infections ◽

Impact Resistance ◽

Acid Synthesis ◽

Type Ii ◽

Content Type ◽

Triclosan Resistance

ABSTRACT The need for new antimicrobials to treat bacterial infections has led to the use of type II fatty acid synthesis (FASII) enzymes as front-line targets. However, recent studies suggest that FASII inhibitors may not work against the opportunist pathogen Staphylococcus aureus, as environmental fatty acids favor emergence of multi-anti-FASII resistance. As fatty acids are abundant in the host and one FASII inhibitor, triclosan, is widespread, we investigated whether fatty acid pools impact resistance in clinical and veterinary S. aureus isolates. Simple addition of fatty acids to the screening medium led to a 50% increase in triclosan resistance, as tested in 700 isolates. Moreover, nonculturable triclosan-resistant fatty acid auxotrophs, which escape detection under routine conditions, were uncovered in primary patient samples. FASII bypass in selected isolates correlated with polymorphisms in the acc and fabD loci. We conclude that fatty-acid-dependent strategies to escape FASII inhibition are common among S. aureus isolates and correlate with anti-FASII resistance and emergence of nonculturable variants.

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Bacterial Targets of Antibiotics in Methicillin-Resistant Staphylococcus aureus

Antibiotics ◽

10.3390/antibiotics10040398 ◽

2021 ◽

Vol 10 (4) ◽

pp. 398

Author(s):

Harshad Lade ◽

Jae-Seok Kim

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Teichoic Acid ◽

Acid Synthesis ◽

Accessory Gene ◽

Methicillin Resistant ◽

Accessory Gene Regulator ◽

Healthcare Settings ◽

Lipid Ii ◽

Novel Therapeutic Strategies

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent bacterial pathogens and continues to be a leading cause of morbidity and mortality worldwide. MRSA is a commensal bacterium in humans and is transmitted in both community and healthcare settings. Successful treatment remains a challenge, and a search for new targets of antibiotics is required to ensure that MRSA infections can be effectively treated in the future. Most antibiotics in clinical use selectively target one or more biochemical processes essential for S. aureus viability, e.g., cell wall synthesis, protein synthesis (translation), DNA replication, RNA synthesis (transcription), or metabolic processes, such as folic acid synthesis. In this review, we briefly describe the mechanism of action of antibiotics from different classes and discuss insights into the well-established primary targets in S. aureus. Further, several components of bacterial cellular processes, such as teichoic acid, aminoacyl-tRNA synthetases, the lipid II cycle, auxiliary factors of β-lactam resistance, two-component systems, and the accessory gene regulator quorum sensing system, are discussed as promising targets for novel antibiotics. A greater molecular understanding of the bacterial targets of antibiotics has the potential to reveal novel therapeutic strategies or identify agents against antibiotic-resistant pathogens.

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Antimicrobial activity of a novel furan fatty acid, 7,10-epoxyoctadeca-7,9-dienoic acid against methicillin-resistant Staphylococcus aureus

Food Science and Biotechnology ◽

10.1007/s10068-016-0257-6 ◽

2016 ◽

Vol 25 (6) ◽

pp. 1671-1675 ◽

Cited By ~ 5

Author(s):

Chakradhar Dasagrandhi ◽

Joel B. Ellamar ◽

Young Soon Kim ◽

Hak-Ryul Kim

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Activity ◽

Fatty Acid ◽

Methicillin Resistant Staphylococcus Aureus ◽

Dienoic Acid ◽

Methicillin Resistant ◽

Furan Fatty Acid

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Permissive Fatty Acid Incorporation in Host Environments Promotes Staphylococcal Adaptation to FASII Antibiotics

10.1101/635698 ◽

2019 ◽

Author(s):

Gérald Kénanian ◽

Claire Morvan ◽

Antonin Weckel ◽

Amit Pathania ◽

Jamila Anba-Mondoloni ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

Acid Synthesis ◽

Human Pathogen ◽

Membrane Phospholipids ◽

Exogenous Fatty Acid ◽

Adaptation Capacity ◽

Future Drug

SummaryDevelopment of fatty acid synthesis pathway (FASII) inhibitors against the major human pathogen Staphylococcus aureus hinges on the accepted but unproven postulate that an endogenously synthesized branched chain fatty acid is required to complete membrane phospholipids. Evidence for anti-FASII efficacy in animal models supported this view. However, restricted test conditions used previously to show FASII antibiotic efficacy led us to investigate these questions in a broader, host-relevant context. We report that S. aureus rapidly adapts to FASII antibiotics without FASII mutations when exposed to host environments. Treatment with a lead FASII antibiotic upon signs of infection, rather than just after inoculation as commonly practiced, failed to eliminate S. aureus from infected organs in a septicemia model. In vitro, addition of serum facilitated rapid S. aureus FASII bypass by environmental fatty acid (eFA) replacement in phospholipids. Serum lowers membrane stress, leading to increased retention of the two substrates required for exogenous fatty acid (eFA) utilization. In these conditions, eFA occupy both phospholipid positions 1 and 2, regardless of anti-FASII selection. This study revises conclusions on S. aureus fatty acid requirements by disproving the postulate of fatty acid stringency, and reveals an Achilles’ heel for using FASII antibiotics to treat infection in monotherapy.Significance statementAntibiotic discovery to overcome treatment failure has huge socio-medical and economic stakes. The fatty acid synthesis (FASII) pathway is considered an ideal druggable target against the human pathogen Staphylococcus aureus, based on evidence of anti-FASII efficacy in infection models, and the postulate that S. aureus synthesizes an irreplaceable fatty acid. We report that S. aureus alters its behavior in host-relevant conditions. Administering FASII antibiotics upon signs of infection, rather than just after inoculation as frequently practiced, failed to clear septicemic infections. In serum, S. aureus rapidly overcomes FASII antibiotics by incorporating alternative fatty acids. We conclude that previously, premature antibiotic treatments and experimental constraints masked S. aureus antibiotic adaptation capacity. These findings should help streamline future drug development programs.

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Ftsh Sensitizes Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics by Degrading YpfP, a Lipoteichoic Acid Synthesis Enzyme

Antibiotics ◽

10.3390/antibiotics10101198 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1198

Author(s):

Won-Sik Yeo ◽

Bohyun Jeong ◽

Nimat Ullah ◽

Majid Ali Shah ◽

Amjad Ali ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Critical Role ◽

Lipoteichoic Acid ◽

Acid Synthesis ◽

Aureus Strain ◽

Methicillin Resistant ◽

Lactam Antibiotic ◽

Membrane Bound ◽

Sensitizing Effect

In the Gram-positive pathogen Staphylococcus aureus, FtsH, a membrane-bound metalloprotease, plays a critical role in bacterial virulence and stress resistance. This protease is also known to sensitize methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics; however, the molecular mechanism is not known. Here, by the analysis of FtsH substrate mutants, we found that FtsH sensitizes MRSA specifically to β-lactams by degrading YpfP, the enzyme synthesizing the anchor molecule for lipoteichoic acid (LTA). Both the overexpression of FtsH and the disruption of ypfP-sensitized MRSA to β-lactams were observed. The knockout mutation in ftsH and ypfP increased the thickness of the cell wall. The β-lactam sensitization coincided with the production of aberrantly large LTA molecules. The combination of three mutations in the rpoC, vraB, and SAUSA300_2133 genes blocked the β-lactam-sensitizing effect of FtsH. Murine infection with the ypfP mutant could be treated by oxacillin, a β-lactam antibiotic ineffective against MRSA; however, the effective concentration of oxacillin differed depending on the S. aureus strain. Our study demonstrated that the β-lactam sensitizing effect of FtsH is due to its digestion of YpfP. It also suggests that the larger LTA molecules are responsible for the β-lactam sensitization phenotype, and YpfP is a viable target for developing novel anti-MRSA drugs.

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