Mol­e­cule has po­ten­tial to save lives

China Daily (Hong Kong) - - PAGE TWO -

in low- and mid­dle-in­come coun­tries.

In March, the UK Health Depart­ment com­mit­ted 10 mil­lion pounds and the Chi­nese Min­istry of Sci­ence and Tech­nol­ogy put for­ward 60 mil­lion yuan ($8.8 mil­lion) to fund a joint com­pe­ti­tion to en­cour­age re­searchers in the UK and China to de­velop so­lu­tions ad­dress­ing the threat posed by AMR.

This year, funds have also been com­mit­ted to a pro­ject in Ar­gentina fo­cus­ing on AMR in agri­cul­ture, the devel­op­ment of a new an­tibi­otic for drug-re­sis­tant gon­or­rhea, and 20 mil­lion pounds went to the Com­bat­ing An­tibi­otic Re­sis­tant Bac­te­ria Bio­phar­ma­ceu­ti­cal Ac­cel­er­a­tor, a pro­ject in the US that sup­ports re­search on the most dan­ger­ous drug-re­sis­tant bac­te­ria.

The drugs don’t work

An­tibi­otics rev­o­lu­tion­ized medicine in the 20th cen­tury. Peni­cillin alone is thought to have saved more than 200 mil­lion lives since it was first used to treat in­fec­tion in 1942.

Most con­ven­tional forms of an­tibi­otics, in­clud­ing peni­cillin and me­thi­cillin, at­tack bac­te­ria by in­hibit­ing the for­ma­tion of cell walls, or by in­ter­rupt­ing vi­tal pro­cesses such as pro­tein syn­the­sis.

Some bac­te­ria de­velop re­sis­tance to an­tibi­otics through ge­netic mu­ta­tions that al­ter ar­eas or pro­cesses tar­geted by med­i­ca­tion.

Over time, these genes pro­lif­er­ate, cre­at­ing en­tire strains of an­tibi­oti­cre­sis­tant bac­te­ria such as me­thi­cillin-re­sis­tant Staphy­lo­coc­cus au­reus, or MRSA.

A study con­ducted last year by the Lon­don School of Hy­giene and Trop­i­cal Medicine sug­gests MRSA is wide­spread in the UK. Over a 12-month pe­riod, 173 sep­a­rate in­fec­tion clus­ters were iden­ti­fied in the east of Eng­land alone.

Ear­lier this year, an out­break of MRSA at a hospi­tal in the Ir­ish cap­i­tal Dublin led to the in­fec­tion of six in­fants and the deaths of two ba­bies born pre­ma­turely.

Vic­to­ria Ware­ham, a se­nior staff nurse at St Thomas’ Hospi­tal in Lon­don, said that a few years ago she would treat a child for a drug-re­sis­tant in­fec­tion on av­er­age once a week. To­day, she said it is not un­com­mon for three or four chil­dren to be ad­mit­ted in a week.

“For some cases, like MRSA, the course of treat­ment can take weeks,” Ware­ham said. “We try to make the bed space as homely as pos­si­ble, but with these kids, the toys they can play with and the li­nen we use is re­ally re­stricted.”

The AMR prob­lem is com­pounded by the fact that new strains keep emerg­ing. Last year in China, a pre­vi­ously un­known drug-re­sis­tant strain of pneu­mo­nia killed five peo­ple at a hospi­tal in Zhe­jiang prov­ince.

Search for a cure

There are 48 reg­is­tered new an­tibi­otics that have the po­ten­tial to com­bat drug re­sis­tance, ac­cord­ing to a database com­piled by the Pew Char­i­ta­ble Trust, a pub­lic pol­icy body in the US.

“Only one out of ev­ery five is likely to make it all the way through to hu­man test­ing,” said Kathy Talk­ing­ton, who heads the AMR pro­ject at the trust. “And only 12 of those in devel­op­ment will treat those pathogens listed by the World Health Or­ga­ni­za­tion as crit­i­cal threats.”

Later this year, Talk­ing­ton will launch a vir­tual lab­o­ra­tory of drug devel­op­ment data to en­able sci­en­tists to dis­cover pat­terns in terms of the most ef­fec­tive drugs against su­per­bugs.

“Our hope is that it makes ev­ery­thing read­ily avail­able so that peo­ple don’t re­peat the same re­search,” Talk­ing­ton said. “We sim­ply don’t have time for those rep­e­ti­tions.”

Some of the most promis­ing re­cent work in the devel­op­ment of the next gen­er­a­tion of treat­ments is un­der­way in the UK and China.

In Septem­ber, Richard Kao Yi-tsun, a mi­cro­bi­ol­o­gist at the Univer­sity of Hong Kong, said he had suc­cess­fully used a com­pound called NP16 to in­hibit the pro­duc­tion of a pig­ment in MRSA. The pig­ment, called staphy­lox­an­thin, helps MRSA to deal with at­tacks from the im­mune sys­tem, and the body can nat­u­rally clear in­fec­tion more eas­ily in its ab­sence.

Martha Clokie, a pro­fes­sor of mi­cro­bi­ol­ogy at the Univer­sity of Le­ices­ter, has had some suc­cess in us­ing viruses called phages to kill E. Coli bac­te­ria, sug­gest­ing that vi­ral ther­apy could be used as an al­ter­na­tive to an­tibi­otics to treat in­fec­tion.

Dong Changjiang, a mi­cro­bi­ol­o­gist from Hubei prov­ince work­ing at the Univer­sity of East Anglia, stud­ies the struc­ture of the outer mem­brane of so-called gram-neg­a­tive bac­te­ria, which in­clude MRSA and E. Coli. Gram-neg­a­tive bac­te­ria are par­tic­u­larly re­sis­tant to an­tibi­otics due to an im­per­me­able lipid-based outer mem­brane.

Dong used in­tense X-rays to map the struc­ture of the outer mem­brane and iden­ti­fied path­ways through which the cell sends “build­ing block” pro­teins to con­struct the mem­brane. He discovered that mol­e­cules can be used to block these path­ways, ren­der­ing the bac­te­ria de­fense­less.

Dong said he is col­lab­o­rat­ing with drug de­sign­ers who might be able to de­velop med­i­ca­tions that ex­ploit what he de­scribes as bac­te­ria’s “Achilles’ heel”.

“Many an­tibi­otics are be­com­ing use­less, caus­ing hun­dreds of thou­sands of deaths each year,” Dong said. “Su­per­bug num­bers are in­creas­ing at an un­ex­pected rate. We want to change that.”

One of the most en­cour­ag­ing AMR projects un­der­way in Bri­tain is the one at the Univer­sity of Lin­coln, where Ish­war Singh and his team have de­vel­oped syn­thetic teixobactin.

In 2015, sci­en­tists in the US discovered teixobactin in soil-dwelling bac­te­ria. These bac­te­ria use the mol­e­cule — com­pris­ing 11 amino acids — as a kind of chem­i­cal weapon to kill other bac­te­ria. Un­like other nat­u­rally oc­cur­ring an­tibi­otic sub­stances such as peni­cillin, teixobactin tar­gets lipids in a bac­te­ria’s cell walls in­stead of pro­teins.

Im­me­di­ately af­ter its dis­cov­ery, teixobactin was found to be ef­fec­tive against sev­eral drug-re­sis­tant strains of bac­te­ria, in­clud­ing MRSA. How­ever, it proved chal­leng­ing to syn­the­size in the lab­o­ra­tory.

To get a drug to mar­ket, it has to be sim­ple and cost ef­fec­tive to man­u­fac­ture, and teixobactin is a complex mol­e­cule. One of its amino acids — the 11 build­ing blocks that make up the mol­e­cule — is rare and not com­mer­cially avail­able. It is pos­i­tively charged and takes 30 hours and mul­ti­ple steps to in­tro­duce dur­ing the syn­theti­za­tion process.

Af­ter years of ex­per­i­ments, Singh and his team made a break­through af­ter “try­ing some­thing that shouldn’t have worked”.

They re­placed the prob­lem amino acid with a dif­fer­ent, com­mer­cially avail­able one that had no charge.

Con­ven­tional wis­dom held that the re­vised teixobactin ana­logue should have fallen apart, but in­cred­i­bly it held to­gether. And it was also more po­tent, killing off su­per­bugs in test tubes more ef­fi­ciently than its nat­u­rally oc­cur­ring cousin.

In March, Singh achieved an­other “quan­tum leap” in the drug’s devel­op­ment. He sent the man­made teixobactin to the Sin­ga­pore Eye Re­search In­sti­tute, where re­searchers suc­cess­fully used it to treat bac­te­rial in­fec­tion in mice.

Singh and his team are now work­ing to fur­ther sim­plify the process of mak­ing the mol­e­cule. He hopes the new an­tibi­otic will go for hu­man test­ing in the next six to 10 years.

“I think it will be used as a last line of de­fense when con­ven­tional an­tibi­otics fail to ad­dress is­sues,” Singh said. “We are not fin­ished yet, but we are ex­cited.”

Many an­tibi­otics are be­com­ing use­less, caus­ing hun­dreds of thou­sands of deaths each year.”

Dong Changjiang, a Chi­nese mi­cro­bi­ol­o­gist work­ing at the Univer­sity of East Anglia

AN­GUS MCNEICE / CHINA DAILY

Ish­war Singh is hope­ful that teixobactin can be used to treat su­per­bug in­fec­tions.

NA­TIONAL IN­STI­TUTE OF AL­LERGY AND IN­FEC­TIOUS DIS­EASE

MRSA bac­te­ria in­ter­act with hu­man white blood cells.

HAN CHUANHAO / XIN­HUA

Promis­ing work in the fight against su­per­bugs is un­der­way in the United King­dom and China.

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