Genesis of Antibiotic Resistance (AR) XLV: Cross‐Resistance Augment AR Pathogens ( ARPath ) as “Clinical Persister”

Here we present three independent experimental evidence from the literature along with a rationale corroborating our hypotheses for a plausible sequence of physiological cascade conferring “C ross Resistance” ( ARPath ) ( at least in part ) leading to the formation “Clinical Persister(s) impinging on cognitive deficiencies in an ensuing psychotic episode(s) . First, based on the studies of 3, 5, 6‐trichloro‐2‐pyridinol (TCP) a breakdown product of Chlorpyrifos (Organophosphorus pesticide) has been suggested to have bactericidal properties as its docking to the active site of Penicillin Biding Proteins(PBP) forming a covalent penicilloyl‐enzyme complex blocking the normal transpeptidation reaction. Henceforth, TCP has been suggested to be an alternative in lieu of antibiotics for treating of Pseudomonas aeruginosa (UTI), Klebsiella pneumonia e (Bacteremia or Septicemia, meningitis , endocarditis , cellulitis , UTIs), E.coli (3MZD) and Streptococcus pneumonia (Pneumonia). Mechanisms such as a . upregulation gene expression to an increased esterases, glutathione transferases and other oxidases production; b . down regulation of pesticide receptors gene expression for a decreased receptor – pesticides complex formation; and c . altered pesticide resistance gene(s) expression has been suggested for the evolution of pesticide resistance in soil microbes. Soil microbes developing tolerance /adaptation to xenobiotic compounds that have similar mechanisms of action as the pesticide to which it was already exposed is referred as cross‐resistance . Second evidence that, when Escherichia coli wt and Salmonella typhimurium wt were treated with sub‐lethal / sub therapeutic dose of herbicide, acquired resistance with a modification the active site of pesticide degrading enzymes. Third evidence, studies on antibiotics docking to the active sites of organophosphorus hydrolase ( Oph ), ( the interaction of Oph with organophosphorus ) resulted in a docking score of −6.902 with five hydroxyl bonds: the hydrogen atoms of organophosphorus interact with TYR128, TYR197 and ASP364 at distances of 2.235 Å, 1.926 Å and 1.703 Å, while the oxygen atoms of organophosphorus interact with GLN278 and ARG328 at distances of 2.171 and 1.851. Taken together, it is suggested that in Step #1: when the soil bacteria exposed to pesticide metabolic breakdown product TCP, TCP confer bactericidal effect. Step #2., bacteria that could withstand excessive / sustained sub lethal concentration of the organophosphate pesticides would develop subsequently develop pesticide resistance. Step #3, when pesticide resistant bacteria are exposed to antibiotics and subsequent docking of antibiotic or its metabolic intermediate to altered active site of Oph would lead to AR. The excess use of pesticide / herbicide in agricultural practices and also the excess use of the antibiotics in the farms animals and misuse in patient care in infectious diseases would compromise the intended therapeutic efficacy while exacerbating AR ( and/or combination of herbicide & pesticide resistance ) as ARP impinging on cognitive disorders in global population. Support or Funding Information Supported by Professional Development Funds by SWTJC to Subburaj Kannan This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .