Editing Penicillin (section)

=== Entry into bacteria ===
Penicillin can easily enter bacterial cells in the case of [[Gram-positive bacteria|Gram-positive species]]. This is because Gram-positive bacteria do not have an outer cell membrane and are simply enclosed in a thick [[cell wall]].<ref>{{cite journal | vauthors = Silhavy TJ, Kahne D, Walker S | title = The bacterial cell envelope | journal = Cold Spring Harbor Perspectives in Biology | volume = 2 | issue = 5 | pages = a000414 | date = May 2010 | pmid = 20452953 | pmc = 2857177 | doi = 10.1101/cshperspect.a000414 }}</ref> Penicillin molecules are small enough to pass through the spaces of [[glycoproteins]] in the cell wall. For this reason Gram-positive bacteria are very susceptible to penicillin (as first evidenced by the discovery of penicillin in 1928<ref name="Fleming1929" />).<ref name=":8">{{cite journal | vauthors = Lambert PA | title = Cellular impermeability and uptake of biocides and antibiotics in Gram-positive bacteria and mycobacteria | journal = Journal of Applied Microbiology | volume = 92 | issue = Suppl | pages = 46S–54S | date = 2002 | pmid = 12000612 | doi = 10.1046/j.1365-2672.92.5s1.7.x | s2cid = 24067247 | doi-access =  }}</ref>

Penicillin, or any other molecule, enters [[Gram-negative bacteria]] in a different manner. The bacteria have thinner cell walls but the external surface is coated with an additional cell membrane, called the outer membrane. The outer membrane is a lipid layer ([[lipopolysaccharide]] chain) that blocks passage of water-soluble ([[hydrophilic]]) molecules like penicillin. It thus acts as the first line of defence against any toxic substance, which is the reason for relative resistance to antibiotics compared to Gram-positive species.<ref>{{cite journal | vauthors = Vergalli J, Bodrenko IV, Masi M, Moynié L, Acosta-Gutiérrez S, Naismith JH, Davin-Regli A, Ceccarelli M, van den Berg B, Winterhalter M, Pagès JM | title = Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria | journal = Nature Reviews. Microbiology | volume = 18 | issue = 3 | pages = 164–76 | date = March 2020 | pmid = 31792365 | doi = 10.1038/s41579-019-0294-2 | s2cid = 208520700 | url = https://discovery.ucl.ac.uk/id/eprint/10092508/3/Acosta%20Gutierrez_Porins%20and%20small-molecule%20translocation%20across%20the%20outer%20membrane%20of%20Gram-negative%20bacteria_AAM.pdf | access-date = 2021-07-30 | archive-date = 2021-10-22 | archive-url = https://web.archive.org/web/20211022163704/https://discovery.ucl.ac.uk/id/eprint/10092508/3/Acosta%20Gutierrez_Porins%20and%20small-molecule%20translocation%20across%20the%20outer%20membrane%20of%20Gram-negative%20bacteria_AAM.pdf | url-status = live }}</ref> But penicillin can still enter Gram-negative species by diffusing through aqueous channels called [[Porin (protein)|porins]] (outer membrane proteins), which are dispersed among the fatty molecules and can transport nutrients and antibiotics into the bacteria.<ref>{{cite book | vauthors = Masi M, Winterhalter M, Pagès JM | title = Bacterial Cell Walls and Membranes | chapter = Outer Membrane Porins | series = Subcellular Biochemistry | volume = 92 | pages = 79–123 | date = 2019 | pmid = 31214985 | doi = 10.1007/978-3-030-18768-2_4 | isbn = 978-3-030-18767-5 | s2cid = 195066847 }}</ref> Porins are large enough to allow diffusion of most penicillins, but the rate of diffusion through them is determined by the specific size of the drug molecules. For instance, penicillin G is large and enters through porins slowly; while smaller ampicillin and amoxicillin diffuse much faster.<ref name=":7">{{cite journal | vauthors = Soares GM, Figueiredo LC, Faveri M, Cortelli SC, Duarte PM, Feres M | title = Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs | journal = Journal of Applied Oral Science | volume = 20 | issue = 3 | pages = 295–309 | date = 2012 | pmid = 22858695 | pmc = 3881775 | doi = 10.1590/s1678-77572012000300002 }}</ref> In contrast, large vancomycin can not pass through porins and is thus ineffective for Gram-negative bacteria.<ref>{{cite journal | vauthors = Antonoplis A, Zang X, Wegner T, Wender PA, Cegelski L | title = Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-Resistant ''E. coli'' and Targets Cell-Wall Synthesis | journal = ACS Chemical Biology | volume = 14 | issue = 9 | pages = 2065–70 | date = September 2019 | pmid = 31479234 | pmc = 6793997 | doi = 10.1021/acschembio.9b00565 }}</ref> The size and number of porins are different in different bacteria. As a result of the two factors—size of penicillin and porin—Gram-negative bacteria can be unsusceptible or have varying degree of susceptibility to specific penicillin.<ref name=":11">{{cite journal | vauthors = Breijyeh Z, Jubeh B, Karaman R | title = Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It | journal = Molecules | volume = 25 | issue = 6 | page = 1340 | date = March 2020 | pmid = 32187986 | pmc = 7144564 | doi = 10.3390/molecules25061340 | doi-access = free }}</ref>