Surviving Reactive Chlorine Stress: Responses of Gram-Negative Bacteria to Hypochlorous Acid

Abstract

Sodium hypochlorite (NaOCl) and its active ingredient, hypochlorous acid (HOCl), are the most commonly used chlorine-based disinfectants. HOCl is a fast-acting and potent antimicrobial agent that interacts with several biomolecules, such as sulfur-containing amino acids, lipids, nucleic acids, and membrane components, causing severe cellular damage. It is also produced by the immune system as a first-line of defense against invading pathogens. In this review, we summarize the adaptive responses of Gram-negative bacteria to HOCl-induced stress and highlight the role of chaperone holdases (Hsp33, RidA, Cnox, and polyP) as an immediate response to HOCl stress. We also describe the three identified transcriptional regulators (HypT, RclR, and NemR) that specifically respond to HOCl. Besides the activation of chaperones and transcriptional regulators, the formation of biofilms has been described as an important adaptive response to several stressors, including HOCl. Although the knowledge on the molecular mechanisms involved in HOCl biofilm stimulation is limited, studies have shown that HOCl induces the formation of biofilms by causing conformational changes in membrane properties, overproducing the extracellular polymeric substance (EPS) matrix, and increasing the intracellular concentration of cyclic-di-GMP. In addition, acquisition and expression of antibiotic resistance genes, secretion of virulence factors and induction of the viable but nonculturable (VBNC) state has also been described as an adaptive response to HOCl. In general, the knowledge of how bacteria respond to HOCl stress has increased over time; however, the molecular mechanisms involved in this stress response is still in its infancy. A better understanding of these mechanisms could help understand host-pathogen interactions and target specific genes and molecules to control bacterial spread and colonization.

Biocide Use in the Antimicrobial Era: A Review

“…Hypochlorous acid (HOCl) is inexpensive, generally toxic and can be used within mouthwashes, sanitizers, clinical disinfection at 1000 ppm, podiatry and as a part of wound care [ 42 ] ( Figure 2 d). Interestingly, it is also generated by the human immune system as part of the initial innate immunity defense against infectious agents [ 43 ].…”

New Clinical Applications of Electrolyzed Water: A Review

“…The concentration of chlorine (Cl 2 , OCl − , and HOCl), ORP, and pH directly play an important role in the antimicrobial efficacy of EW (shown in the Figure 3 ). HOCl is the most effective inactivation compound in the chlorine group [ 66 ]. They found that the inactivation efficacy of HOCl was 80-fold higher than that of an equivalent concentration of OCl − when the pH value of the solution was from 5.0 to 6.5.…”

Genome-Wide Screening of Oxidizing Agent Resistance Genes in Escherichia coli

“…Expression of sanA is implicated in strengthening membrane permeability in stationary-phase stress responses [60]. It is reasonable that these three genes encode proteins in membrane systems, as HOCl has been found to damage the cell envelope system of bacteria [19]. Besides them, we also identified eight genes (marC, ybhR, exbD, yfdY, motB, yoaE, hyaC, and tap), which encode proteins in membrane systems.…”

“…For HOCl, bacteria have developed different defense mechanisms, such as converting Hsp33, RidA, and CnoX into highly active chaperones to prevent proteins from aggregation and degradation caused by HOCl [17,18]. HOCl-responsive transcriptional factors such as HypT, RclR, and NemR can also help to alleviate HOCl damages [19]. For instance, HypT can be activated by oxidation of its methionine residues and then upregulate the transcription of genes participating in the biosynthesis of amino acids such as methionine (metB, metK, and metN), while downregulating intracellular iron levels [20].…”