Inhibitory Effects of Lipophilic Acids and Related Compounds on Bacteria and Mammalian Cells

Abstract

The inhibitory effect of lipophilic acids, antimicrobial food additives, and analgesics-antipyretics was examined at concentrations from 0.1 to 100 mM in bacteria ( Bacillus subtilis and Escherichia coli ) and mammalian cells (HeLa, human fibroblasts, and mouse neuroblastoma cells). Most compounds inhibit the growth of HeLa cells about as efficiently as that of B. subtilis . However, butyrate and propionate, as well as acetaminophen, antipyrene, phenacetin, and salicylamide, inhibit HeLa at millimolar concentrations whereas, at least 10 times higher concentrations are needed to inhibit B. subtilis . The concentrations needed to inhibit growth by 50% decrease with increasing octanol-water partition coefficients of the compound. Growth of E. coli is inhibited similar to that of B. subtilis by all compounds except butylbenzoate, decanoate, and linoleate which cannot penetrate the lipopolysaccharide layer. All growth inhibitors inhibit amino acid uptake into bacteria and their vesicles, and oxygen consumption in bacteria. In HeLa cells or human fibroblasts, neither amino acid uptake nor adenine 5′-triphosphate synthesis are inhibited by fatty acids at concentrations that completely inhibit growth. Short chain fatty acids (propionate, butyrate, and pentanoate) induce in HeLa the formation of cell processes. In neuroblastoma cells, grown in the presence of 10% fetal calf serum, butyrate also induces such processes which slowly continue to grow in length for at least 7 days; these processes differ in speed of formation, width, and cycloheximide susceptibility from the thin processes produced by serum deprivation alone.

Pancytopenia in Propionic Acidemia: Hematologic Evaluation and Studies of Hematopoiesis in Vitro

“…Both these compounds have been found to inhibit growth of bacteria, HeLa cells (20), and chick embryo fibroblasts (21), to reversibly inhibit histone deacetylase (22,23), and to modify growth-related processes of several transformed cell lines (24,25). Butyrate has been shown to arrest cell growth at G, phase of cell cycle (26), to alter size and shape of rabbit articular chondrocytes with formation ofbinucleated cells (27), and to disrupt nuclear and cytoskeletal elements of several cell types (28).…”

Inhibition of Escherichia coli growth by acetic acid: a problem with methionine biosynthesis and homocysteine toxicity

“…The antimicrobial activities of many different weak acid food preservatives have been well documented (Eklund, 1980 ;Sheu et al, 1972Sheu et al, , 1975. Their toxicity is multifactorial and includes : the ability of the undissociated acid to diffuse freely across lipid bilayers and liberate protons in the cytoplasm, lowering the cytoplasmic pH (Booth, 1985) ; the intercalation of the undissociated acid into the lipid bilayer at low external pH (Stratford & Anslow, 1998) ; and the consequences of anion accumulation (Russell & Diez-Gonzales, 1998 ;Roe et al., 1998).…”

Effect of short-chain fatty acids on growth of the ruminal bacterium Streptococcus bovis.

“…it decreases as the chain length decreases, in the order butyric > propionic > acetic (Table 1). At the membrane level, VFAs have the potential to inhibit the transport of amino acids and ketoacids (21). Intracellularly, VFAs can act as catabolic repressors of the synthesis or inhibitors of the activity of enzymes involved in energy-yielding fermentative pathways.…”

“…The mechanism of inhibition is as follows: undissociated VFAs are lipophilic molecules (21) and, therefore, they are able to diffuse through the cell membrane: due to a more alkaline intracellular pH, VFAs are deprotonated and the anions-that can not travel across the membraneaccumulate inside the cell (18). Because VFAs and lactic acid have pKa< 5.0, at pH 6.5, they are mainly dissociated and, therefore, are unable to permeate into cells.…”

“…1, 0.2, and 0.3 M of acetic, propionic, butyric, and lactic acids are greater at pH 5.5 than at pH 6.5 are coherent with the increased permeability of the cells to these compounds at the former pH level (undissociated acids). The ability of a substance to solubilize and diffuse through the bacterial membrane and, hence, its ability to inhibit growth would be expected to increase with its hydrophobicity (21) . In this respect, it is noteworthy that, at concentrations of 0.1 M and higher, the extent of inhibition by VFAs followed the same order as the degree of hydrophobicity of the VFAs; i.e.…”