## 3 Protective and Repair Mechanisms against Acid Stress  
Bacteria can deploy several protective and repair mechanisms to reduce the detrimental effects that low pH has on membranes, proteins and DNA. Many bacteria are capable of changing their membrane fatty acid profile in response to acidic conditions [49; 50; 51]. _E. coli_ can increase the concentration of cyclopropane fatty acids (CFA) present in the cell membrane in order to decrease membrane permeability [52; 53]. This requires a specific enzyme, the cyclopropane fatty acyl phospholipid synthase (CFAS), a soluble enzyme that is capable of transferring a methyl group from S-adenosyl methionine to unsaturated fatty acid molecules already present in the bacterial inner membrane [54; 55]. The ability of _E.coli_ to survive at pH 3.0 is correlated with the level of CFAs in the membrane [49] and _cfa_ mutants are more sensitive to acid shock [52]. CFAs contribute to acid tolerance by decreasing membrane proton permeability and enhancing the ability to extrude protons [53]. How CFAs affect membrane properties like fluidity and permeability is not well understood. Recently, a molecular dynamics simulation suggested a dual role for CFAs: these lipids can stabilise cell membranes against adverse conditions and at the same time promote membrane fluidity [56]. The role that other cell membrane components play in acid stress resistance mechanisms in _E. coli_ has been reviewed recently by [PERSON] et al. [57]. Other mechanisms to adjust membrane fatty acid composition under acid stress conditions have been described in Gram-positive bacteria. _L. monocytogenes_ has an atypically high content of branched-chain fatty acids (BCFAs), and its ability to modulate the relative proportions of different BCFAs, allows the bacteria to adapt to moderate pH stress [58]. _L. monocytogenes_ cells grown in the presence of various acids incorporated more saturated fatty acids and less BCFAs into their membranes, thus decreasing the membrane fluidity in response to acid stress [59]. Most recently the two component system CpxRA of _E. coli_ has been shown to contribute to growth in moderate acidic conditions (pH 4.0-5.0) by upregulating the transcription of _fabA_ and _fabB_, genes involved in the production of unsaturated fatty acids [60] (Figure 1A). Although the mechanisms underlying the modification of the membrane lipid composition in _E. coli_ and _L. monocytogenes_ under acidic conditions are somewhat different, the overall effect observed as a result of this change seem to be the remodeling of the membrane, maintaining its integrity and fluidity while conferring protection against acid stress. Proteins in the bacterial periplasmic space are more vulnerable to acidic conditions than proteins in the cytoplasm, because of the relative permeability of the outer membrane porins to small molecules [61]. HdeA and HdeB are two periplasmic chaperones that play an essential role in _E. coli_ during acid stress [62; 63]. These proteins prevent protein aggregation induced by low pH and high periplasmic chloride concentrations and assist in the re-folding process of their substrates during pH neutralization [62; 63; 64; 65]. Proteins in the periplasm cannot access the intracellular ATP pool and need to rely on an energy independent mechanism to fulfil their function. Both chaperones exist as functionally inactive dimers at neutral pH, but a decrease in pH triggers a dimer to monomer transition and partial protein unfolding, exposing a large hydrophobic surface that interacts with unfolded substrate proteins [62; 66; 67; 63]. While HdeA is active at pH below 3, HdeB exhibits its highest chaperone activity at pH 4 [68]. The presence of both chaperones appears to enable _E. coli_ to rapidly respond to a broader range of acid stress conditions, minimizing the irreversible aggregation of acid-unfolded proteins [68]. The cytoplasmic molecular chaperone Hsp31 also contributes to acid resistance in stationary phase _E. coli_[69].