Plen­tisillin and Peni­cillin: An An­tibi­otic Spoof and a Tragedy

by Ronald Bent­ley and Joan W. Ben­nett

The year 1946 was one in which it was pos­si­ble for many of the world's peo­ples to have a hope­ful view for the fu­ture. The hor­rors of World War II were over and re­build­ing was in progress. Inter­national travel re­sumed and, as fleets of air­planes were con­structed, be­came some­what eas­ier than pre­vi­ously. A new world-wide or­ga­ni­za­tion, The United Na­tions, had been es­tab­lished and the Gen­eral As­sem­bly and Se­cu­rity Coun­cil held their first meet­ings in Jan­u­ary of that year. In sci­en­tific dis­ci­plines, new tech­nolo­gies stem­ming from the war-time in­ves­ti­ga­tions of the re­lease of atomic en­ergy, were trans­form­ing re­search. The an­a­lyt­i­cal work that would even­tu­ally lead to the dou­ble he­lix struc­ture for DNA and the very ex­ten­sive use of biotech­nol­ogy was un­der­way.

A cul­ture of a peni­cillin-pro­duc­ing Peni­cillium and the struc­ture of peni­cillin G. Source: Dept. of Phar­ma­ceu­ti­cal Sci­ences In­sti­tute for Phar­ma­ceu­ti­cal Bi­ol­ogy, Ba­sel, Switzer­land

In med­i­cine, a ma­jor de­vel­op­ment was the an­tibi­otic re­volution lead­ing to the con­trol of many, pre­vi­ously in­tractable, in­fec­tious dis­eases. Sig­nif­i­cant amounts of peni­cillin for civil­ian use be­came avail­able in the USA in 1945 and the UK in 1946 (Bud, 2007). In­deed, peni­cillin can now be con­sid­ered as a com­mod­ity chem­i­cal (Bent­ley and Ben­nett, 2008). An or­ga­ni­za­tion for the re­lief of war-dev­as­tated coun­tries, The United Na­tions Re­lief and Re­ha­bil­i­ta­tion Agency (UNRRA), had been es­tab­lished and, be­gin­ning in 1946, pro­vided an­tibi­otic ex­per­tise and even en­tire peni­cillin pro­duc­tion plants to sev­eral na­tions (Bud, 2007). Slowly, an­tibi­otic use be­came a world-wide phe­nom­e­non and the term, an­tibi­otic, came into the com­mon vo­cab­u­lary.

An an­tibi­otic was seen as a mirac­u­lous drug that was a more or less gen­eral cure-all, pre­scribed even to treat the com­mon cold. More­over, fol­low­ing a mas­sive and se­cret re­search pro­gram in the USA and the UK, the chem­i­cal struc­ture of peni­cillin had been de­ter­mined and be­came gen­er­ally known in 1946.

An in­di­ca­tion of the wide­spread pub­lic­ity for an­tibi­otics was a preprint dis­trib­uted at the AAAS Meet­ing, March 27−30, 1946, with a typ­i­cal cover of the kind used for Sci­ence. This re­port an­nounced the dis­cov­ery and char­ac­ter­i­za­tion of plen­tisillin – a ma­te­r­ial iso­lated from ba­nana peel with the unique prop­erty of hav­ing no an­tibi­otic ac­tiv­ity what­so­ever. Re­mark­ably, it con­tained deu­terium, ²H, in ad­di­tion to the usual el­e­ments, C, H, N, O and S. It was, of course, an elab­o­rate spoof, with the Sci­ence vol­ume num­ber be­ing given as ℑ. The au­thor used a pseu­do­nym, Nor­man Nadir, the lat­ter an ana­gram for Radin, at that time a grad­u­ate stu­dent at Co­lum­bia University's Col­lege of Physi­cians and Sur­geons. Hap­pily, Radin went on to have a suc­cess­ful ca­reer as a bio­chemist with many se­ri­ous pub­li­ca­tions. The par­ody has been reprinted (We­ber, 1987).

Radin's post-war par­ody was in­tended as a joke. A half-cen­tury later it is no joke at all that sev­eral an­tibi­otics have lost or are los­ing their ef­fec­tive­ness.

Like plen­tisillin, they es­sen­tially have be­come ma­te­ri­als lack­ing an­tibi­otic ac­tiv­ity. Af­ter some 6 decades of the very in­ten­sive use of an­tibi­otics, many in­fec­tions have been cured, many lives have been saved. Be­gin­ning in the 1950s, some or­gan­isms that pre­vi­ously were eas­ily con­trolled by an­tibi­otics ac­quired re­sis­tance to these ma­te­ri­als. Early hopes that the re­sis­tance phe­nom­e­non could be con­trolled by the de­vel­op­ment of new, syn­thetic or semi-syn­thetic, an­tibi­otics or by iso­lation of newly dis­cov­ered com­pounds, have been ful­filled only par­tially. Now, at the be­gin­ning of the 21st cen­tury, re­sis­tance to an­tibi­otics is, in­deed, a se­ri­ous prob­lem.

A dra­matic ex­am­ple is the treat­ment of in­fec­tions due to Neis­se­ria gon­or­rhoeae, about 800,00 of which oc­cur each year in the USA alone (Wang et al., 2007). Be­gin­ning in 1936, un­com­pli­cated gon­or­rhea could be con­trolled with sul­fon­amides, but by 1945 one third of strains were re­sis­tant. Peni­cillin came to the res­cue. A dose of 50,000 units ini­tially pro­vided a one-day cure but in 1972 it was nec­es­sary to use a much larger amount of peni­cillin, 4.8 × 10⁶ units. As the in­evitable resis­tance spread, both peni­cillin and tetra­cy­clines were aban­doned in the 1980s as gon­or­rhea thera­pies in the USA (Wang et al., 2007). The re­place­ment ther­a­pies were cephalosporins and fluoro­quinolones. How­ever, flu­o­ro­quinolone-re­sis­tant strains have spread world wide (Tap­sall, 2001) and a spe­cial Gono­coc­cal Iso­late Sur­veil­lance Project (GISP) was funded by the Cen­ters for Dis­ease Con­trol and Pre­ven­tion to mon­i­tor USA trends in flu­o­ro­quinolone re­sis­tance (Wang et al., 2007). It goes with­out say­ing that re­sis­tance in­creased with in­creased use of the flu­o­ro­quinolones. An in­ter­est­ing find­ing was that af­ter peni­cillin treat­ment was dis­con­tin­ued, preva­lence of peni­cillin re­sis­tant strains has de­clined.

Ini­tially, gono­cocci were very sus­cep­ti­ble to oral ciprofloxacin with MIC (min­i­mum in­hibitory val­ues) about 0.06 mg·L^-1. These val­ues in­creased, first to 1 mg·L^-1 and later be­came as high as 16–32 mg·L^-1 (Tap­sall, 2001). In a re­cent Mor­bid­ity and Mor­tal­ity Weekly Re­port (April 13, 2007) came grim news: CDC an­nounced that flu­o­ro­quinolones were no longer rec­om­mended for treat­ment of gono­coc­cal in­fec­tions. Now the only rec­om­mended treat­ment is the use of cephalosporins. Un­fortunately, these an­tibi­otics are ex­pen­sive and of­ten re­quire in­jec­tion (Wang et al., 2007).

An­other prob­lem con­cerns a semi-syn­thetic peni­cillin, me­thi­cillin. This an­tibi­otic re­sem­bles the com­mon peni­cillin G (ben­zylpeni­cillin) but the phenyl group has been re­placed with a dimethoxy­phenyl group – hence the 'meth' com­po­nent of the name. It was de­vel­oped by the Beecham com­pany; the process from dis­cov­ery to launch (1960) was re­mark­able, re­quir­ing only a few months (Bud, 2007). How­ever, within a year, a me­thi­cillin-re­sis­tant Staphy­lo­coc­cus au­reus strain was dis­cov­ered at Queen Mary's, a large children's hos­pi­tal near Lon­don. This or­gan­ism, with the acronym, MRSA (Me­thi­cillin-Re­sis­tant Staphy­lo­coc­cus Au­reus) be­came in­creas­ingly com­mon in hos­pi­tals. These Gram-pos­i­tive bac­te­ria have ac­quired lev­els of re­sis­tance that trans­form a pre­viously eas­ily treat­able ill­ness into a po­ten­tially lethal sep­ticemia. In hos­pi­tal set­tings, trans­plant pa­tients and the el­derly are most at risk. More­over, prob­lems with MRSA have spread to the ge­neral com­mu­nity lead­ing to the term, Com­mu­nity Ac­quired MRSA (CA-MRSA).

A Wash­ing­ton Post ar­ti­cle (Oc­to­ber 17, 2007) notes that MRSA is now more deadly than the AIDS virus; the head­line reads: Drug-Re­sis­tant Staph Germ's Toll Is Higher Than Thought. The ar­ti­cle cites 94,000 se­ri­ous in­fec­tions and nearly 19,000 deaths each year. The ar­ti­cle was oc­ca­sioned by the death of a 17 year-old foot­ball player, with the nec­es­sary clos­ing of 21 schools in Bed­ford County, VA, for clean­ing in the hope of pre­vent­ing other cases. That the vic­tim was a foot­ball player is no­table since CA-MRSA of­ten in­volves ath­letes, prison in­mates and chil­dren.

Or­gan­isms re­sis­tant to other, po­tent an­tibi­otics in­creas­ingly have been iden­ti­fied. In­deed, the so-called "an­tibi­otic of last re­sort", van­comycin, is now vul­ner­a­ble. It is in­deed ironic that the name, van­comycin, was de­rived from words re­lated to "van­quished" (e.g., French, vain­cre, to con­quer). Pre­scrip­tion prac­tices drive the evo­lu­tion of drug re­sis­tance. The more an­tibi­otics are used the greater the Dar­win­ian se­lec­tion pres­sure on strains with ever higher lev­els of re­sis­tance. A com­plete de­scrip­tion of the prob­lem of an­tibi­otic re­sis­tance is be­yond the scope of this es­say. How­ever, two re­cent books with very telling ti­tles, are mines of in­for­ma­tion. They are Re­venge of the Mi­crobes: How Bac­te­r­ial Re­sis­tance is Un­der­min­ing the An­tibi­otic Rev­o­lu­tion (Saly­ers and Whitt, 2005) and Peni­cillin: Tri­umph and Tragedy (Bud, 2007). They should be re­quired read­ing for any­one in­ter­ested in the treat­ment of in­fec­tious dis­ease.

Ref­er­ences

Bent­ley, R., and Ben­nett, J. W. 2008. A fer­ment of fer­men­ta­tions: re­flec­tions on the pro­duc­tion of com­mod­ity chem­i­cals by mi­croor­gan­isms. Adv. Appl. Mi­cro­biol., 63, in press.

Bud, R. 2007. Peni­cillin: Tri­umph and Tragedy. Ox­ford Uni­ver­sity Press, Ox­ford.

Saly­ers, A. A., and Whitt, D. D. 2005. Re­venge of the Mi­crobes: How Bac­te­r­ial Re­sis­tance is Un­der­min­ing the An­tibi­otic Rev­o­lu­tion. ASM Press, Wash­ing­ton, DC.

Tap­sall, J. 2001. An­timi­cro­bial re­sis­tance to Neis­se­ria gon­or­rhoeae. WHO/CDS/DRS 2001.3:16. World Health Or­ga­ni­za­tion, Geneva.

Wang, S. A. et al. 2007. An­timi­cro­bial re­sis­tance for Neis­se­ria gon­or­rhoeae in the United States, 1988 to 2003: the spread of flu­o­ro­quinolone re­sis­tance. Ann. Int. Med. 147, 81–89.

We­ber, R. L. Droll Sci­ence. 1987. Hu­mana Press, Clifton, NJ.

Ronald Bent­ley is a Pro­fes­sor Emer­i­tus, De­part­ment of Bi­o­log­i­cal Sci­ences, Uni­ver­sity of Pitts­burgh. Joan Ben­nett is a Pro­fes­sor at the De­part­ment of Plant Bi­ol­ogy & Pathol­ogy, Rut­gers Uni­ver­sity. She is also As­so­ciate VP for the Pro­mo­tion of Women in Sci­ence, En­gi­neer­ing and Math­e­mat­ics, and a Past Pres­i­dent of the ASM.